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STUDY QUESTION What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? SUMMARY ANSWER We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. WHAT IS KNOWN ALREADY OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. STUDY DESIGN, SIZE, DURATION We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses’ Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. MAIN RESULTS AND THE ROLE OF CHANCE Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). LIMITATIONS, REASONS FOR CAUTION Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. STUDY FUNDING/COMPETING INTEREST(S) The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. TRIAL REGISTRATION NUMBER N/A

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses’ Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0–14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio = 0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause.

Key Points Question What is the association of parity and breastfeeding with early natural menopause? Findings In this cohort study that included 108 887 premenopausal women, parity and breastfeeding were each associated with a significantly lower risk of early natural menopause. Findings for breastfeeding suggest that some of the lower risk attributed to parity could be attributable to breastfeeding. Meaning The findings suggest that breastfeeding at levels consistent with current recommendations may confer an additional benefit of lower risk of early menopause., This cohort study examines the association of parity and breastfeeding with the risk of early natural menopause among women in the Nurses’ Health Study II cohort., Importance Pregnancy and breastfeeding prevent ovulation and may slow the depletion of the ovarian follicle pool. These factors may lower the risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. Objective To examine the association of parity and breastfeeding with the risk of early menopause. Design, Setting, and Participants This population-based cohort study within the Nurses’ Health Study II cohort (1989-2015) included premenopausal participants who were aged 25 to 42 years at baseline. Response rates were 85% to 90% for each cycle, and follow-up continued until menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, loss to follow-up, or end of follow-up in May 2015. Hypotheses were formulated after data collection. Data analysis took place from February to July 2019. Exposures Parity (ie, number of pregnancies lasting ≥6 months) was measured at baseline and every 2 years. History and duration of total and exclusive breastfeeding were assessed 3 times during follow-up. Menopause status and age were assessed every 2 years. Main Outcomes and Measures Risk of natural menopause before age 45 years. Results At baseline, 108 887 premenopausal women aged 25 to 42 years (mean [SD] age, 34.1 [4.6] years; 102 246 [93.9%] non-Hispanic white) were included in the study. In multivariable models, higher parity was associated with lower risk of early menopause. Hazard ratios were attenuated with adjustment for breastfeeding but remained significant. Compared with nulliparous women, those reporting 1, 2, 3, and 4 or more pregnancies lasting at least 6 months had hazard ratios for early menopause of 0.92 (95% CI, 0.79-1.06), 0.84 (95% CI, 0.73-0.96), 0.78 (95% CI, 0.67-0.92), and 0.81 (95% CI, 0.66-1.01), respectively (P for trend = .006). In multivariable models also adjusted for parity, hazard ratios for duration of exclusive breastfeeding of 1 to 6, 7 to 12, 13 to 18, and 19 or more months were 0.95 (95% CI, 0.85-1.07), 0.72 (95% CI, 0.62-0.83), 0.80 (95% CI, 0.66-0.97), and 0.89 (95% CI, 0.69-1.16), respectively, compared with less than 1 month of exclusive breastfeeding (P for trend = .001). Despite the significant test for trend, estimates were not observed to be lower as duration of exclusive breastfeeding increased. In a stratified analysis of parous women, risk of early menopause was lowest among those reporting exclusive breastfeeding for 7 to 12 months in each level of parity (women with 2 pregnancies and 7-12 months of breastfeeding: HR, 0.79; 95% CI, 0.66-0.96; ≥3 pregnancies and 7-12 months of breastfeeding: HR, 0.68; 95% CI, 0.52-0.88; 2 pregnancies and ≥13 months of breastfeeding: HR, 0.87; 95% CI, 0.66-1.15; ≥3 pregnancies and 13-18 months of breastfeeding: HR, 0.86; 95% CI, 0.66-1.13; and ≥3 pregnancies and ≥19 months of breastfeeding: HR, 0.98; 95% CI, 0.72-1.32). Conclusions and Relevance In this study, an inverse association of parity with risk of early menopause was observed. Breastfeeding was associated with significantly lower risk, even after accounting for parity. Breastfeeding at levels consistent with current recommendations may confer an additional benefit of lower risk of early menopause.

Crohn’s disease is a chronic inflammatory bowel disease (IBD) with a high rate of complications that frequently lead to a decreased quality of life. Despite our better understanding of disease pathophysiology and treatment over the past three decades, the risk of intestinal complications and need for resultant surgery have not changed significantly.1 Fortunately, newer treatments and more aggressive treatment algorithms are showing promise with higher rates of clinical remission. Specifically, the earlier use of anti-tumor necrosis factor (TNF) and immunomodulator (IM) therapy may be able to alter the natural history of Crohn’s disease and prevent complications before they develop.2–4 Enthusiasm over the use of these agents earlier in the disease course is tempered by the concern of side-effects associated with immune suppression. Patients and parents appear willing to accept risks of adverse events including life-threatening infections and lymphoma, but this is dependent upon the expectation that the disease is severe (i.e., they “deserve the treatment”), and that treatment will be effective.5, 6 If we were able to identify the patients who are at the most risk from their disease, then it would allow us to more easily justify using our most effective therapies sooner. Conversely, patients at low risk can be spared exposure to potentially toxic medications. Clinical and serologic factors have been identified that appear to serve as predictors of disease severity.7, 8 Although useful in helping to risk stratify patients, the results of these studies are presented as relative statistical comparisons (e.g., odds ratios, hazard ratios, p-values), which are difficult to translate clearly for patients so that they understand the implications of their disease. A tool to present more clearly individual absolute disease risk and predicted response to therapy in real-time would enhance a provider’s ability to communicate with patients and their families. System dynamics analysis (SDA) is a methodology that addresses the inherent dynamic complexity of interactions between variables. Used more commonly in the fields of economics and engineering, SDA has had limited use in medicine.9, 10 Advantages of SDA over traditional statistical methods are that it can provide real-time individualized predictions of outcomes, it uses a straightforward control panel to input variables, and it can create simple graphs to convey predicted outcomes over time. Applied to medicine, SDA may have the ability to translate complex clinical data into patient friendly results. Using a cohort of pediatric Crohn’s disease patients with detailed clinical and serologic profiles we developed a model to predict the individualized risk of complicated Crohn’s disease and how this risk is modified by treatment. SDA provides a graphic display of these results for a real-time visual explanation predicting disease outcome with or without medical therapy.

Background: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. Methods: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 ± 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 ± 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. Results: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6–73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30–60]) versus those who did not, (0 points [IQR 0–10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90–0.97). Test–retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84–0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92–0.99]; standardized response mean 2.66). Conclusion: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC. (Inflamm Bowel Dis 2009)

Background: Variation in care is a ubiquitous feature of medical practice and may lead to significant differences in health care costs, quality, and outcomes. We undertook this study to determine the extent of intercenter variation in the initial management of children newly diagnosed with Crohn’s disease. Methods: We analyzed the utilization of 5 classes of medication (immunomodulators, prednisone, antibiotics, 5-aminosalicylates, and infliximab) among 311 children with newly diagnosed Crohn’s disease followed at 10 North American pediatric gastroenterology centers. Multivariate logistic regression was used to compare the utilization rate of each class of medication at each of the 10 centers, adjusting for potential confounders including patient age, sex, race, disease severity, and anatomic location of disease. Results: Median utilization of each class of medication was: immunomodulators, 56% (range 29%–97%); prednisone, 78% (range 32%– 88%); antibiotics, 29% (range 11%– 68%); 5-aminosalicylates, 63.5% (range 18%–92%); and infliximab, 7.5% (range 3%–21%). Each of these treatments showed statistically significant intercenter variation in utilization (P 0.001 for immunomodulators, prednisone, antibiotics, and 5-ASA; P 0.02 for infliximab). After adjusting for the demographic and clinical factors listed above, intercenter variation remained significant; however, the low utilization of infliximab precluded multivariate analysis. Conclusions: Widespread intercenter variation in the medical management of newly diagnosed children with Crohn’s disease was observed, even after adjusting for possible differences in case mix between institutions. This variation may lead to unintended differences in health care costs and outcomes. (Inflamm Bowel Dis 2007;13:890 – 895)

Although it is known that extraintestinal manifestations (EIMs) commonly occur in pediatric inflammatory bowel disease (IBD), little research has examined rates of EIMs and their relation to other disease-related factors in this population. The purpose of this study was to determine the rates of EIMs in pediatric IBD and examine correlations with age, sex, diagnosis, disease severity, and distribution.Data were prospectively collected as part of the Pediatric IBD Collaborative Research Group Registry, an observational database enrolling newly diagnosed IBD patients16 years old since 2002. Rates of EIM (occurring anytime during the period of enrollment) and the aforementioned variables (at baseline) were examined. Patients with indeterminate colitis were excluded from the analysis given the relatively small number of patients.One thousand nine patients were enrolled (mean age 11.6 +/- 3.1 years, 57.5% boys, mean follow-up 26.2 +/- 18.2 months). Two hundred eighty-five (28.2%) patients experienced 1 or more EIMs. Eighty-seven percent of EIM occurred within the first year. Increased disease severity at baseline (mild vs moderate/severe) was associated with the occurrence of any EIM (P0.001), arthralgia (P = 0.024), aphthous stomatitis (P = 0.001), and erythema nodosum (P = 0.009) for both Crohn disease (CD) and ulcerative colitis (UC) during the period of follow-up. Statistically significant differences in the rates of EIMs between CD and UC were seen for aphthous stomatitis, erythema nodosum, and sclerosing cholangitis.EIMs as defined in this study occur in approximately one quarter of pediatric patients with IBD. Disease type and disease severity were commonly associated with the occurrence of EIMs.

Background: We sought to characterize perianal disease and its treatment in pediatric patients newly diagnosed with Crohn's disease. Methods: Data were obtained from the Pediatric Inflammatory Bowel Disease (IBD) Collaborative Group Registry, a prospective, multicenter observational registry recording clinical and laboratory outcomes in children under 16 years of age newly diagnosed with IBD. Patients with Crohn's disease were selected who had data on perianal disease and at least 24 months of follow-up. The records of patients with a Pediatric Crohn's Disease Activity Index perianal subscore greater than 0 were reviewed, and patients with abscesses or fistulas were selected. The therapies used and the course of their perianal disease were then assessed. Results: Of the 276 patients identified, 41 had perianal lesions within 30 days of diagnosis. Thirteen of these had skin tags and fissures only, whereas 28 had fistulas and/or abscesses. The latter lesions resolved by 1 year in 20 patients, and 8 had chronic/recurrent perianal disease persisting for more than 1 year following diagnosis. Patients with fistulizing disease were much more likely to be treated and were treated earlier with antibiotics, infliximab, and immunomodulators than were nonfistulizing patients. Patients who developed chronic perianal disease were more likely to have low body mass indices and required more perianal surgery than did patients whose perianal disease resolved. Conclusions: Approximately 10% of newly diagnosed pediatric patients with Crohn's disease will have perianal fistulas and/or abscesses at the time of diagnosis. Most of these will resolve within a year with medical therapy alone. (Inflamm Bowel Dis 2008)

The ability to identify children with CD who are at highest risk for rapid progression from uncomplicated to complicated phenotypes would be invaluable in guiding initial therapy. The aims of this study were to determine whether immune responses and/or CARD15 variants are associated with complicated disease phenotypes and predict disease progression.Sera were collected from 796 pediatric CD cases and tested for anti-Cbir1 (flagellin), anti-outer membrane protein C, anti-Saccharomyces cerevisiae, and perinuclear antineutrophil cytoplasmic antibody by using enzyme-linked immunosorbent assay. Genotyping (Taqman MGB) was performed for 3 CARD15 variants (single nucleotide polymorphisms 8, 12, and 13). Associations between immune responses (antibody sum and quartile sum score, CARD15, and clinical phenotype were evaluated.Thirty-two percent of patients developed at least 1 disease complication within a median of 32 months, and 18% underwent surgery. The frequency of internal penetrating, stricturing, and surgery significantly increased (P trend.0001 for all 3 outcomes) with increasing antibody sum and quartile sum score. Nine percent of seropositive groups had internal penetrating/stricturing versus 2.9% in the seronegative group (P = .01). Twelve percent of seropositive groups underwent surgery versus 2% in the seronegative group (P = .0001). The highest antibody sum group (3) and quartile sum score group (4) demonstrated the most rapid disease progression (P.0001). Increased hazard ratio was observed for antibody sum group 3 (7.8; confidence interval, 2.2-28.7), P.002 and quartile sum score group 4 (11.0; confidence interval, 1.5-83.0, P.02).The rate of complicated CD increases in children as the number and magnitude of immune reactivity increase. Disease progression is significantly faster in children expressing immune reactivity.

OBJECTIVE. The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease. METHODS. Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorized by physician global assessment. RESULTS. A total of 526 children (mean age: 11.6 years; 58% male; 392 with Crohn disease and 134 with ulcerative colitis) were studied. All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50%, and albumin levels for 60%. There was no clear association between Crohn disease location and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests. CONCLUSION. The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease.

Background & Aims We examined the incidence of Crohn's disease (CD)-related surgery in a multi-center, inception cohort of pediatric patients with CD. We also examined the effect of starting immunomodulator therapy within 30 days of diagnosis. Methods Data from 854 children with CD from the Pediatric Inflammatory Bowel Disease Collaborative Research Group who were diagnosed with CD between 2002 and 2008 were analyzed. Results Overall, 76 (9%) underwent a first CD-related surgery, 57 (7%) underwent a first bowel surgery (bowel resection, ostomy, strictureplasty, or appendectomy), and 19 (2%) underwent a first non-bowel surgery (abscess drainage or fistulotomy). The cumulative risks for bowel surgery, non-bowel surgery, and all CD-related surgeries were 3.4%, 1.4%, and 4.8%, respectively, at 1 year after diagnosis and 13.8%, 4.5%, and 17.7%, respectively, at 5 years after diagnosis. Older age at diagnosis, greater disease severity, and stricturing or penetrating disease increased the risk of bowel surgery. Disease between the transverse colon and rectum decreased the risk. Initiation of immunomodulator therapy within 30 days of diagnosis, sex, race, and family history of inflammatory bowel disease did not influence the risk of bowel surgery. Conclusions In an analysis of pediatric patients with CD, the 5-year cumulative risk of bowel surgery was lower than that reported in recent studies of adult and pediatric patients but similar to that of a recent retrospective pediatric study. Initiation of immunomodulator therapy at diagnosis did not alter the risk of surgery within 5 years of diagnosis.

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.