Long-term outcomes of switching to gonadotrophins versus continuing with clomiphene citrate, with or without intrauterine insemination, in women with normogonadotropic anovulation and clomiphene failure: follow-up study of a factorial randomized clinical trial.

STUDY QUESTION: What are the long-term outcomes after allocation to use of gonadotrophins versus clomiphene citrate (CC) with or without IUI in women with normogonadotropic anovulation and clomiphene failure? SUMMARY ANSWER: About four in five women with normogonadotropic anovulation and CC failure had a live birth, with no evidence of a difference in pregnancy outcomes between the allocated groups. WHAT IS KNOWN ALREADY: CC has long been used as first line treatment for ovulation induction in women with normogonadotropic anovulation. Between 2009 and 2015, a two-by-two factorial multicentre randomized clinical trial in 666 women with normogonadotropic anovulation and six cycles of CC failure was performed (M-ovin trial). This study compared a switch to gonadotrophins with continued treatment with CC for another six cycles, with or without IUI within 8 months. Switching to gonadotrophins increased the chance of conception leading to live birth by 11% over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. The addition of IUI did not significantly increase live birth rates. STUDY DESIGN, SIZE, DURATION: In order to investigate the long-term outcomes of switching to gonadotrophins versus continuing treatment with CC, and undergoing IUI versus continuing with intercourse, we conducted a follow-up study. The study population comprised all women who participated in the M-ovin trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participating women were asked to complete a web-based questionnaire. The primary outcome of this study was cumulative live birth. Secondary outcomes included clinical pregnancies, multiple pregnancies, miscarriage, stillbirth, ectopic pregnancy, fertility treatments, neonatal outcomes and pregnancy complications. MAIN RESULTS AND THE ROLE OF CHANCE: We approached 564 women (85%), of whom 374 (66%) responded (184 allocated to gonadotrophins; 190 to CC). After a median follow-up time of 8 years, 154 women in the gonadotrophin group had a live birth (83.7%) versus 150 women in the CC group (78.9%) (relative risk (RR) 1.06, 95% CI 0.96-1.17). A second live birth occurred in 85 of 184 women (49.0%) in the gonadotrophin group and in 85 of 190 women (44.7%) in the CC group (RR 1.03, 95% CI 0.83-1.29). Women allocated to gonadotrophins had a third live birth in 6 of 184 women (3.3%) and women allocated to CC had a third live birth in 14 of 190 women (7.4%). There were respectively 12 and 11 twins in the gonadotrophin and CC groups. The use of fertility treatments in the follow-up period was comparable between both groups. In the IUI group, a first live birth occurred in 158 of 192 women (82.3%) and while in the intercourse group, 146 of 182 women (80.2%) reached at least one live birth (RR: 1.03 95% CI 0.93-1.13; 2.13%, 95% CI -5.95, 10.21). LIMITATIONS, REASONS FOR CAUTION: We have complete follow-up results for 57% of the women.There were 185 women who did not respond to the questionnaire, while 102 women had not been approached due to missing contact details. Five women had not started the original trial. WIDER IMPLICATIONS OF THE FINDINGS: Women with normogonadotropic anovulation and CC failure have a high chance of reaching at least one live birth. In terms of pregnancy rates, the long-term differences between initially switching to gonadotrophins are small compared to continuing treatment with CC. STUDY FUNDING/COMPETING INTEREST(S): The original study received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). A.H. reports consultancy for development and implementation of a lifestyle App, MyFertiCoach, developed by Ferring Pharmaceutical Company. M.G. receives unrestricted grants for scientific research and education from Ferring, Merck and Guerbet. B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy for ObsEva and Merck and travel support from Merck. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: This follow-up study was registered in the OSF Register, https://osf.io/pf24m. The original M-ovin trial was registered in the Netherlands Trial Register, number NTR1449.

Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter?

STUDY QUESTION: Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles? SUMMARY ANSWER: Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles. WHAT IS ALREADY KNOWN: For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins. STUDY DESIGN, SIZE, DURATION: Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC. PARTICIPANTS/MATERIALS, SETTING, METHODS: EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER). MAIN RESULTS AND THE ROLE OF CHANCE: Mid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13-2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75-1.29). LIMITATIONS, REASONS FOR CAUTION: This was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women. WIDER IMPLICATIONS OF THE FINDINGS: In women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT > 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs. STUDY FUNDING/COMPETING INTEREST(S): The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Netherlands Trial Register, number NTR1449.

Gonadotrophins versus clomiphene citrate with or without IUI in women with normogonadotropic anovulation and clomiphene failure: a cost-effectiveness analysis.

STUDY QUESTION: Are six cycles of ovulation induction with gonadotrophins more cost-effective than six cycles of ovulation induction with clomiphene citrate (CC) with or without IUI in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC? SUMMARY ANSWER: Both gonadotrophins and IUI are more expensive when compared with CC and intercourse, and gonadotrophins are more effective than CC. WHAT IS KNOWN ALREADY: In women with normogonadotropic anovulation who ovulate but do not conceive after six cycles with CC, medication is usually switched to gonadotrophins, with or without IUI. The cost-effectiveness of these changes in policy is unknown. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation of ovulation induction with gonadotrophins compared with CC with or without IUI in a two-by-two factorial multicentre randomized controlled trial in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC. Between December 2008 and December 2015 women were allocated to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse. The primary outcome was conception leading to a live birth achieved within 8 months of randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a cost-effectiveness analysis on direct medical costs. We calculated the direct medical costs of ovulation induction with gonadotrophins versus CC and of IUI versus intercourse in six subsequent cycles. We included costs of medication, cycle monitoring, interventions, and pregnancy leading to live birth. Resource use was collected from the case report forms and unit costs were derived from various sources. We calculated incremental cost-effectiveness ratios (ICER) for gonadotrophins compared to CC and for IUI compared to intercourse. We used non-parametric bootstrap resampling to investigate the effect of uncertainty in our estimates. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: We allocated 666 women in total to gonadotrophins and IUI (n = 166), gonadotrophins and intercourse (n = 165), CC and IUI (n = 163), or CC and intercourse (n = 172). Mean direct medical costs per woman receiving gonadotrophins or CC were €4495 versus €3006 (cost difference of €1475 (95% CI: €1457-€1493)). Live birth rates were 52% in women allocated to gonadotrophins and 41% in those allocated to CC (relative risk (RR) 1.24:95% CI: 1.05-1.46). The ICER was €15 258 (95% CI: €8721 to €63 654) per additional live birth with gonadotrophins. Mean direct medical costs per woman allocated to IUI or intercourse were €4497 versus €3005 (cost difference of €1510 (95% CI: €1492-€1529)). Live birth rates were 49% in women allocated to IUI and 43% in those allocated to intercourse (RR = 1.14:95% CI: 0.97-1.35). The ICER was €24 361 (95% CI: €-11 290 to €85 172) per additional live birth with IUI. LIMITATIONS, REASONS FOR CAUTION: We allowed participating hospitals to use their local protocols for ovulation induction and IUI, which may have led to variation in costs, but which increases generalizability. Indirect costs generated by transportation or productivity loss were not included. We did not evaluate letrozole, which is potentially more effective than CC. WIDER IMPLICATIONS OF THE FINDINGS: Gonadotrophins are more effective, but more expensive than CC, therefore, the use of gonadotrophins in women with normogonadotropic anovulation who have not conceived after six ovulatory CC cycles depends on society's willingness to pay for an additional child. In view of the uncertainty around the cost-effectiveness estimate of IUI, these data are not sufficient to make recommendations on the use of IUI in these women. In countries where ovulation induction regimens are reimbursed, policy makers and health care professionals may use our results in their guidelines. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by the Netherlands Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). The Eudract number for this trial is 2008-006171-73. The Sponsor's Protocol Code Number is P08-40. CBLA reports unrestricted grant support from Merck and Ferring. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva and Guerbet. TRIAL REGISTRATION NUMBER: NTR1449.

Endometrial thickness in women undergoing IUI with ovarian stimulation. How thick is too thin? A systematic review and meta-analysis.

STUDY QUESTION: Is pre-ovulatory endometrial thickness (EMT) in women with unexplained subfertility undergoing IUI with ovarian stimulation (OS) associated with pregnancy chances? SUMMARY ANSWER: We found no evidence for an association between EMT and pregnancy chances. WHAT IS KNOWN ALREADY: It has been suggested that OS with clomiphene citrate (CC) results in a lower EMT than with gonadotrophins or aromatase inhibitors, but the clinical consequences in terms of pregnancy are unclear. STUDY DESIGN, SIZE, DURATION: We performed a systematic review and meta-analysis of studies comparing CC, gonadotrophins or aromatase inhibitors in an IUI program reporting on EMT and pregnancy rates in women with unexplained subfertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched MEDLINE, EMBASE and the non-MEDLINE subset of PubMed from inception to 28th June 2016 and cross-checked references of relevant articles. Outcome measures were clinical pregnancy rate and mean pre-ovulatory EMT. We calculated mean differences (MD) with 95% CIs with a fixed effect model, and in case of heterogeneity with an I2 > 50% a random effect model. We performed a meta-regression analysis to determine if stimulating drugs interacted with the estimated effect of EMT. MAIN RESULTS AND THE ROLE OF CHANCE: Our search retrieved 1563 articles of which 23 were included, totaling 3846 women. There were 17 RCTs and 6 cohort studies. The average study quality was low and there was considerable to substantial statistical heterogeneity. Seven studies provided data on EMT in relation to pregnancy. There was no evidence of a difference in EMT between women who conceived and women that did not conceive (1525 women, MDrandom: 0.51 mm, 95% CI: -0.05 to 1.07). Women treated with CC had a significantly thinner EMT than women treated with gonadotrophins (two studies, MD: -0.33, 95% CI: -0.64 to -0.01). There was no evidence of a difference in EMT when comparing CC with letrozole (five studies, MDrandom: -0.84, 95% CI: -1.97 to 0.28). The combination of CC plus gonadotrophins resulted in a slightly thinner endometrium than letrozole (nine studies, MDrandom: -0.79, 95% CI: -1.37 to -0.20). Letrozole resulted in a thinner EMT than gonadotrophins (two studies, MDrandom: -1.31, 95% CI: -2.08 to -0.53). LIMITATIONS, REASONS FOR CAUTION: The overall quality of the included studies was low to moderate. We found considerable to substantial heterogeneity in the comparisons, hampering firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: We found no evidence for an association between EMT and pregnancy rates during IUI -OS. As a consequence, canceling IUI cycles because of a thin endometrial lining may negatively affect clinical care. Although we found some evidence for very small differences in EMT when comparing various drugs, we cannot make inferences on their effect on pregnancy chances since these differences may be coincidental. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: N/A.

Pneumonia and the incidence of cancer: a Danish nationwide cohort study.

OBJECTIVES: To examine the risk of a subsequent pulmonary or extra-pulmonary cancer diagnosis following a first-time hospital-based diagnosis of pneumonia. DESIGN: Population-based cohort study using Danish medical registries. SETTING: All hospitals in Denmark. SUBJECTS: A total of 342,609 patients with a first-time hospital-based (inpatient, emergency room or outpatient clinic) diagnosis of pneumonia between 1995 and 2011. MAIN OUTCOME MEASURES: We quantified the excess risk of various cancers amongst pneumonia patients compared to the expected risk in the general population, using relative [standardised incidence ratios (SIRs)] and absolute risk calculations. Follow-up started 1 month after a hospital-based diagnosis of pneumonia and ended on 31 December 2011. RESULTS: A total of 28,496 cancers were observed, compared with 21,625 expected, amongst 342,609 pneumonia patients followed for a median of 4.2 years. The absolute risk of a cancer diagnosis 1 to <6 months following a pneumonia diagnosis was 1.4%, with a corresponding SIR of 2.48 [95% confidence interval (CI) 2.41-2.55]. This was mainly due to an increased risk of lung cancer (eightfold) and haematological cancers (fourfold). The SIR for any cancer remained increased at 1.35 (95% CI 1.30-1.40) during 6-12 months of follow-up, and 1.20 (95% CI 1.18-1.22) during 1-5 years of follow-up. Beyond 5 years, an increased risk was maintained for lung, oesophageal, liver and bladder cancers, squamous cell carcinoma of the skin, lymphoma and multiple myeloma. CONCLUSIONS: A hospital-based pneumonia diagnosis was associated with an increased risk of a cancer diagnosis, especially in the ensuing months, but the absolute risk was small.

How long should we continue clomiphene citrate in anovulatory women?

STUDY QUESTION: What is the effectiveness of continued treatment with clomiphene citrate (CC) in women with World Health Organization (WHO) type II anovulation who have had at least six ovulatory cycles with CC but did not conceive? SUMMARY ANSWER: When women continued CC after six treatment cycles, the cumulative incidence rate of the ongoing pregnancy rate was 54% (95% CI 37-78%) for cycles 7-12. WHAT IS KNOWN ALREADY: If women with WHO type II anovulation fail to conceive with CC within six ovulatory cycles, guidelines advise switching to gonadotrophins, which have a high risk of multiple gestation and are expensive. It is however not clear what success rate could be achieved by continued treatment with CC. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of women with WHO II anovulation who visited the fertility clinics of five hospitals in the Netherlands between 1994 and 2010. We included women treated with CC who had had at least six ovulatory cycles without successful conception (n = 114) after which CC was continued using dosages varying from 50 to 150 mg per day for 5 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follow-up was a total of 12 treatment cycles. Primary outcome was the cumulative incidence rate of an ongoing pregnancy at the end of treatment. MAIN RESULTS AND THE ROLE OF CHANCE: We recruited 114 women that had ovulated on CC for at least six cycles but had not conceived. Of these 114 women, 35 (31%) had an ongoing pregnancy resulting in a cumulative incidence rate of an ongoing pregnancy of 54% after 7-12 treatment cycles with CC. LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are its retrospective approach. WIDER IMPLICATIONS OF THE FINDINGS: Randomized trials comparing continued treatment with CC with the relatively established second line treatment with gonadotrophins are justified. In the meantime, we suggest to only begin this less convenient and more expensive treatment for women who do not conceive after 12 ovulatory cycles with CC. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

Assessment of incidence of inhibitors in patients with haemophilia.

In patients with haemophilia, the development of neutralizing allo-antibodies ('inhibitors') while receiving the deficient clotting factor is relatively common during the patients' initial treatment. Among treated patients with haemophilia who do not develop inhibitors early on, the later incidence is considerably lower. Therefore, the evaluation of potential risk factors for their tendency to give rise to inhibitors is best performed separately in previously untreated and previously treated patients. We discuss potential implications of study design and analysis choices on the validity of inferences from studies assessing inhibitor incidences.

Chronic kidney disease in long-term survivors of hematopoietic cell transplant.

We conducted a cohort study to identify risk factors of chronic kidney disease (CKD) among long-term survivors of hematopoietic cell transplant (HCT). We studied 1635 patients transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1991 and 2002, who survived to day +131 after transplant and had serum creatinine measured on at least two occasions after day +131. CKD was defined as a glomerular filtration rate < 60 ml/min/m(2) on two occasions separated by at least 30 days between days 100 and 540 post transplant. Cox regression models estimated hazard ratios (HRs) describing associations between demographic data, clinical variables and the risk of developing CKD. A total of 376 patients (23%) developed CKD at a median of 191 days post transplant (range 131-516 days). An increased risk of CKD was associated with acute renal failure (ARF) (HR=1.7, 95% confidence interval (CI) 1.3-2.1), acute graft-vs-host disease (aGVHD) grade II (HR=2.0, 95% CI 1.4-2.9) and grades III/IV (HR=3.1, 95% CI 2.1-4.6) and chronic GVHD (HR=1.8, 95% CI 1.4-2.2). Total body irradiation (TBI) (HR=1.0, 95% CI 0.8-1.3) was not associated with an increased risk of CKD. CKD is relatively common among survivors of HCT. The presence of ARF and GVHD, but not receipt of TBI, appears to be associated with the occurrence of CKD.

Neonatal abstinence syndrome and early childhood morbidity and mortality in Washington state: a retrospective cohort study.

OBJECTIVE: The objective of the study was to evaluate the association between neonatal abstinence syndrome (NAS) and long-term childhood morbidity and infant mortality. STUDY DESIGN: We conducted a cohort study of infants born in Washington State during 1990 to 2008 who were diagnosed with NAS (n=1900) or were unexposed (n=12,283, frequency matched by birth year). 5-year hospital readmissions and infant mortality were ascertained. RESULTS: Children with history of NAS had increased risk of readmission during the first 5 years of life relative to unexposed children; this remained statistically significant after adjustment for maternal age, maternal education, gestational age and intrapartum smoking status (readmission rates: NAS=21.3%, unexposed=12.7%, adjusted relative risk (aRR) 1.54, 95% confidence interval (CI) 1.37 to 1.73). NAS was associated with increased unadjusted infant mortality risk, but this did not persist after adjustment (aRR 1.94, 95% CI 0.99 to 3.80). CONCLUSION: The observed increased risk for childhood hospital readmission following NAS diagnosis argues for development of early childhood interventions to prevent morbidity.Journal of Perinatology advance online publication,.

Women's perspectives on ovulation induction with or without IUI as treatment for normogonadotrophic anovulation: a discrete choice experiment.

STUDY QUESTION: What are the treatment preferences of women with normogonadotrophic anovulation treated with ovulation induction with or without intrauterine insemination (IUI)? SUMMARY ANSWER: Women with normogonadotrophic anovulation differ in their treatment preference; half of them base their preference on the lowest burden and half of them on the highest effectiveness. WHAT IS KNOWN ALREADY: Common treatments for anovulatory women who wish to conceive are ovulation induction using clomiphene citrate or letrozole taken in tablet form or with injections containing gonadotrophins, all optionally combined with IUI. Patient preferences for these alternatives have not yet been examined in these women. STUDY DESIGN SIZE AND DURATION: Between August 2014 and February 2017 we conducted a multicentre discrete choice experiment (DCE). The target sample size was calculated by including 20 women for six attributes in the main analysis resulting in the inclusion of 120 women to be able to assess heterogeneity across choices. PARTICIPANTS/MATERIALS SETTING METHODS: We invited treatment-naive women diagnosed with normogonadotropic anovulation and visiting the outpatient clinic of five Dutch centers (three teaching hospitals and two university hospitals) to participate in the DCE by completing a printed questionnaire. We asked women to indicate their preference in hypothetical alternative treatment scenarios by offering a series of choice sets from which they were to choose their preferred alternatives. The choice sets contained several treatment characteristics of interest, i.e. attributes concerning ovulation induction with clomiphene citrate or letrozole versus gonadotrophins, as well as intercourse and IUI. We selected six attributes: number of visits to the outpatient clinic during treatment; type of medication; intercourse or IUI; risk of side effects; willingness to pay; and pregnancy chances leading to the birth of a child after six treatment cycles.We used a multinominal logit model to determine the preferences of women and investigated heterogeneity in preferences through latent class analysis. To determine if women were willing to make a trade-off for higher pregnancy rates at the expense of a higher burden, we calculated the marginal rate of substitution. MAIN RESULTS AND THE ROLE OF CHANCE: The questionnaire was completed by 145 women. All six attributes influenced women's treatment preferences and those valued as most important were low risk of side effects, a minimal number of hospital visits and intercourse. A total of 55% of women were driven by the wish to conceive with the least medical interference and lowest burden. The remaining women were success driven and chose mainly for the highest chances to conceive, regardless of the burden. Age and duration of subfertility did not significantly differ between these women. Women were willing to trade-off some burden and costs for higher pregnancy chances. LIMITATIONS REASONS FOR CAUTION: The sample size of our study is relatively small which made it not possible to perform interaction tests and subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results may be used during the counseling of couples about their treatment options. These findings are an argument to explore if a woman prefers potentially fast success or a medically less intense route that might take longer. The preference for the less intense route would lead to the continuation of ovulation induction with oral drugs such as clomiphene citrate or letrozole rather than treatment with injected gonadotrophins, or even IVF. STUDY FUNDING/COMPETING INTERESTS: B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. CBL reports grants from Merck and Ferring. TRIAL REGISTRATION NUMBER: None.

Serum bilirubin and colorectal cancer risk: a population-based cohort study.

BACKGROUND: Bilirubin has antioxidant properties and has been postulated to protect against the development of malignancies. AIM: To investigate whether baseline serum bilirubin concentration predicts the incidence of colorectal cancer in a nationally representative sample of the US population. METHODS: Participants of the first National Health and Nutrition Examination Survey were divided into four groups based on quartiles of baseline serum bilirubin concentration in mg/dL: <0.38 (n = 1410), 0.38 to <0.5 (n = 1287), 0.5 to <0.6 (n = 1048) and > or = 0.6 (n = 1742). The incidence of colorectal cancer during the following 20 years was determined from hospitalization records and death certificates. RESULTS: 110 cases of colorectal cancer-related death or hospitalization were identified among 5487 participants during 88,339 person-years of follow-up (12 per 10,000 person-years). There was no association between baseline serum bilirubin concentration and the incidence of colorectal cancer either in unadjusted analyses or after adjusting for age, gender, ethnicity, smoking, body mass index, alcohol consumption and educational attainment. CONCLUSIONS: Baseline serum bilirubin concentration did not predict the subsequent incidence of colorectal cancer in this population-based cohort study.

Incidence of histologic types of cancer of the small intestine.

Data from nine population-based cancer registries participating in the Surveillance, Epidemiology, and End Results Program from 1973 through 1982 were analyzed to determine the demographic correlates of the incidence of the four major histologic types of cancer of the small intestine: carcinomas, malignant carcinoid tumors, lymphomas, and sarcomas. These tumors were uncommon: The average annual incidence per million persons was 3.9, 2.9, 1.6, and 1.2, respectively. The age-specific incidence rate for each type was quite low through middle age, after which it rose sharply. Males experienced higher rates than females for each of the four histologic types. Blacks were at a 40-70% greater risk than whites for the occurrence of carcinomas and carcinoid tumors but at a 50% lower risk for lymphomas. The reported incidence of malignant carcinoid tumors increased during the decade under study, the rate at the end of the interval being 50% greater than that at the beginning. The extent to which this increase represents improved detection of these tumors or a change in the criteria separating malignant from benign tumors could not be evaluated. There was no change in the incidence of carcinomas, lymphomas, or sarcomas of the small intestine. The four histologic types varied considerably with regard to their proportional distribution among the subsites of the small intestine. Carcinoid tumors, lymphomas, and sarcomas rarely occurred in the duodenum, whereas nearly half of the carcinomas were found there. Eighty-seven percent of the carcinoid tumors and 60% of the lymphomas occurred in the ileum. Clues to the etiologies of tumors of the small intestine are sparse. The incidence data presented here suggest that at least some of the etiologies will differ among the histologic types.

Second cancers in patients with chronic lymphocytic leukemia.

Among 419 persons diagnosed as having chronic lymphocytic leukemia (CLL) in western Washington State between 1974 and 1983 and followed through January 1985, 9 subsequently developed other lymphoid cancers and 48 developed nonlymphoid cancers. Only 2 lymphoid and 21 nonlymphoid cancers were expected based on the rates of the western Washington population as a whole. Lung cancer accounted for about one-third of the excess rate observed. Three of the nonlymphoid tumors that occurred in the patients with CLL were classified as malignant fibrous histiocytomas, which represents an exceptionally high relative incidence for this histologic type. The excess risk of nonlymphoid cancers was present in both sexes, across all age categories, and in every length-of-follow-up interval. These results, taken together with those obtained from earlier investigations, suggest that persons with CLL are at increased risk of developing a second tumor, particularly in the lung. The reasons for this increased risk remain to be elucidated.

Epidemiology of borderline ovarian tumors.

Ovarian tumors of low malignant potential, often termed "borderline tumors," have been defined as those that have some but not all of the morphologic features of malignancy (i.e., they are not invasive). With the use of data obtained by the western Washington population-based Cancer Surveillance System for 1975-83, the incidence of serous and mucinous borderline epithelial ovarian tumors was analyzed, as well as the survival of women who developed them. The incidence of borderline tumors increased with increasing age, although at a pace somewhat slower than that of malignant ovarian tumors. There was an upward trend in the incidence of borderline tumors starting in the late 1970's, a trend not present for malignant tumors. Only 12% of borderline tumors were not confined to the ovary, as opposed to 40% of malignant Grade I and 73% of other malignant ovarian neoplasms. At 5 years following diagnosis, the survival of women with borderline tumors was 93% that of the general female population. This percentage varied little by stage or histologic type. Given the reduced survival of women with these ovarian tumors and the lack of a sharp histologic distinction between borderline and Grade I malignant lesions, it is recommended that borderline ovarian tumors be routinely ascertained by population-based cancer registries.

Cutaneous melanoma in relation to exogenous hormones and reproductive factors.

Eighty-seven women of ages 37-74, who resided in King County, Wash., and who had been diagnosed between July 1976 and November 1979 as having cutaneous malignant melanoma, were interviewed regarding prior use of estrogen-containing preparations and reproductive history. The responses were compared with those of a random sample of 863 women from the same county. Among the 61 women with superficial spreading melanoma (SSM), use of oral contraceptives for 5 years or more was more common than among controls. The estimated relative risks for users of 5-9 and 10 years or more were 2.4 and 3.6, respectively. No differences between cases and controls were noted for oral contraceptive use of 4 years or less. Giving birth to a first child after age 30 was also associated with an increased relative risk of SSM. Although the positive findings regarding oral contraceptive use and age at birth of first child must be interpreted cautiously pending results of other studies, they suggest that hormonal factors can play a role in the etiology of SSM.

PIP: 87 women ages 37-74 who resided in King County, Washington, and who had been diagnosed between July 1976-November 1979 as having cutaneous malignant melanoma, were interviewed regarding prior use of estrogen-containing preparations and reproductive history. The responses were compared with those of a random sample of 863 women from the same county. Among the 61 women with superficial spreading melanoma (SSM), use of oral contraceptives (OCs) for 5 years or more was more common than among controls. The estimated relative risks for users of 5-9 and 10 years or more were 2.4 and 3.6, respectively. No differences between cases and controls were noted for OC use of 4 or fewer years. Giving birth to a 1st child after age 30 was also associated with an increased relative risk of SSM. Although the positive findings regarding OC use and age at birth of 1st child must be interpreted cautiously pending results of other studies, they suggest that hormonal factors can play a role in SSM etiology.

Marital status and incidence of ovarian cancer: the U.S. Third National Cancer Survey, 1969--71.

As determined in the U.S. Third National Cancer Survey, 1969--71, the incidence of ovarian cancer was 60-70% higher in women who had never married than in those who had. This relationship was present in both whites and blacks and in all age groups over 25 years. Among ovarian epithelial tumors, those for which the incidence rates between never-married and ever-married women differed most were endometrioid and clear cell tumors. The incidence of tumors of germ cell and sex cordmesenchyme origin, however, showed no relationship to marital status.

Incidence of vulvar carcinoma in relation to menstrual, reproductive, and medical factors.

Fifty-seven female residents of King and Pierce Counties (Washington State) with a new diagnosis of in situ or invasive vulvar carcinoma during 1976-79 were interviewed concerning their menstrual, reproductive, and medical histories. A random sample of women residing in the same area was interviewed for comparison. A greater proportion of women with in situ vulvar tumors than control subjects were of low educational level, reported a history of oral contraceptive use, experienced early age at first birth, late age at menopause, and were current or former cigarette smokers. Menstrual and reproductive factors were similar between women with invasive vulvar cancer and controls, but a greater proportion of cases reported a history of diabetes and of cigarette smoking. The factors found in this study to be associated with in situ vulvar carcinoma are similar to those observed among women with cervical cancer. In addition, since the vulva and cervix both are derived from cloacal tissue, and neoplasms of the two sites occur together more often than would be expected by chance, in situ vulvar and cervical tumors may share some common etiologies.

Incidence of thyroid cancer in women in relation to previous exposure to radiation therapy and history of thyroid disease.

Female residents of 13 counties of Western Washington, in whom papillary, follicular, or mixed papillary-follicular thyroid carcinomas had been diagnosed between 1974 and 1979 were interviewed regarding their medical and reproductive histories and past exposure to radiation treatments. For comparison, a random sample of women from the same population was interviewed. Women who had received radiation treatments to the head or neck prior to 5 years before interview were 16.5 times (95% confidence interval = 8.1-33.5) more likely than unexposed women to develop cancer. The relative risk (RR) was highest for papillary cancer (19.4) but also was elevated substantially for follicular and mixed papillary-follicular tumors. Women first irradiated at age 19 years or younger had a much higher RR than did women irradiated at age 20 or older. Regardless of prior radiation exposure, women who ever had had a goiter were at increased risk of developing thyroid cancer. Women who had ever developed a goiter had 17 times the risk of developing follicular cancer and almost 7 times the risk of developing papillary cancer as compared with women who never had had a goiter. Risk of thyroid cancer was elevated even among women who had had a history of goiter many years prior to diagnosis. A history of thyroid nodules was also a risk factor for papillary and mixed thyroid cancer. Neither a history of hypothyroidism nor hyperthyroidism was found to increase the risk of thyroid cancer.

Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors.

Female resident of King and Pierce Counties (Washington) in whom carcinoma of the colon or rectum was diagnosed during a 15-month period in 1976-77 were interviewed regarding their menstrual and reproductive histories. A random sample of women from the same population was interviewed for comparison. On the average, women with colon cancer had given birth to fewer children than had controls; compared to the incidence of colon cancer in nulliparous women, the incidence in women with 1 or 2 children was reduced by 30%, whereas the incidence in women with 3 or more children was reduced by 50% (P=0.004). No association was present between parity and rectal cancer. Neither contraceptive nor noncontraceptive estrogen use was related to the incidence of colon cancer. Use of oral contraceptives was more common among women with rectal cancer than among controls, but this result could well have arisen by chance (P=0.09). The data were not adequate to determine whether it was the inability to conceive and deliver a child that was related to colon cancer or the failure to undergo the physiologic changes that accompany pregnancy. Nonetheless, the association of low parity with the incidence of colon cancer has now observed several times, in each instance to a moderately strong degree. This observation suggests that events of reproductive life have a bearing on a woman's subsequent risk of developing colon cancer.

Incidence of endometrial carcinoma in King County, Washington: a standardized histologic review.

Previously diagnosed tumor specimens from 35- to 74-year-old female patients with endometrial cancer who were residents of King County, Washington, during the first 6 months of 1975 were reviewed by a single pathologist using uniform criteria for the assessment of cancer. Routinely reported incidence of this tumor in this population was judged to be inflated, the annual incidence rate (excluding carcinoma in situ) falling from 108.2 to 88.5 per 100,000 women after the exclusion of cases found not to be unequivocally malignant. This rate nonetheless represented a large increase over the rate of 47.3 per 100,000 observed in the U.S. Third National Cancer Survey just 5 years earlier. We concluded that U.S. pathologists in the 1970's may have been using more liberal criteria by which to diagnose endometrial cancer, but that such a change could only account for a small part of the rising incidence of the disease.