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Objective(s): We estimated the prevalence of requiring specific examinations or tests before providing contraception in a nationwide survey of family planning providers., Study Design: We conducted a cross-sectional survey of public-sector health centers and office-based physicians providing family planning services across the United States in 2019 (n = 1395). We estimated the weighted proportion of providers (or their health center or practice) who required blood pressure measurement, pelvic examination (bimanual examination and cervical inspection), Papanicolaou (Pap) smear, clinical breast examination (CBE), and chlamydia and gonorrhea (CT/GC) screening before initiating hormonal or intrauterine contraception (IUC) for healthy women. We performed multivariable regression to identify factors associated with pelvic examination practices aligned with clinical recommendations; these recommendations classify examinations and tests as recommended or unnecessary before initiation of specific contraceptive methods., Results: The overall response rate was 51%. Most providers required blood pressure measurement before initiating each method. Unnecessary CBE, Pap smears, and CT/GC screening were required by 14% to 33% of providers across methods. Fifty-two to 62% of providers required recommended pelvic examination before IUC placement; however, 16% to 23% of providers required unnecessary pelvic examinations before non-intrauterine hormonal method initiation. Factors associated with recommendation-aligned pelvic examination practices included having a higher proportion of patients using public funding (Medicaid or other assistance) and more recently completing formal clinical training., Conclusions: Almost half (47%) of providers did not require necessary pelvic examination before placing IUC. Conversely, many providers required unnecessary examinations and tests before contraception initiation for patients., Implications: Most providers required the few recommended examinations and tests for safe contraceptive provision. Reduction of unnecessary examinations and tests may reduce barriers to contraceptive access. There are also opportunities to increase use of recommended examinations, as up to 48% of providers did not require recommended pelvic examination before IUC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To describe characteristics of U.S. contraceptive non-users to inform tailored contraceptive access initiatives., Study Design: We used National Survey of Family Growth data from 2011 to 2017 to identify characteristics of contraceptive non-users compared to other women ages 15-44 at risk for unintended pregnancy. We also examined reasons for not using contraception by when non-users expected their next birth. We calculated unadjusted and adjusted prevalence ratios using two definitions of contraceptive non-use: (1) contraceptive non-use during the interview month, and (2) a more refined definition based on contraception use during the most recent month of sexual intercourse and expectation of timing of next birth. We considered p-values < 0.05 statistically significant., Results: Approximately 20% ( n  = 2844) of 12,071 women at risk of unintended pregnancy were classified as standard contraceptive non-users. After adjusting for all other variables, non-users were more likely to be low-income, uninsured, never married, expect a birth within 2 years, and have zero or one parity. The top reasons for contraceptive non-use were not minding if they got pregnant (22.6%), worried about contraceptive side effects (21.0%), and not thinking they could get pregnant (17.6%). After applying the more refined non-user definition, we identified 5.7% ( n  = 721) of women as non-users; expecting a birth within 2-5 years and having a parity of one were associated with non-use after adjustment of all other factors., Conclusion: Our more refined definition of non-users could be used in future studies examining the causes of unintended pregnancy and to inform programmatic interventions to reduce unintended pregnancy., Implications: Describing contraceptive non-users and reasons for contraceptive non-use could help us better understand reasons for unintended pregnancy and inform tailored contraceptive access initiatives., Competing Interests: The authors have no conflicts of interest to disclose., (© 2020 The Authors.)

Background: The World Health Organization (WHO) recommends that women wait at least 24 months after a livebirth before attempting a subsequent pregnancy to reduce the risk of adverse maternal, perinatal, and infant health outcomes. However, the applicability of the WHO recommendations for women in the United States is unclear, as breast feeding, nutrition, maternal age at first birth, and total fertility rate differs substantially between the United States and the low- and middle-resource countries upon which most of the evidence is based., Methods: To inform guideline development for birth spacing specific to women in the United States, the Office of Population Affairs (OPA) convened an expert work group meeting in Washington, DC, on 14-15 September 2017 among reproductive, perinatal, paediatric, social, and public health epidemiologists; obstetrician-gynaecologists; biostatisticians; and experts in evidence synthesis related to women's health., Results: Presentations and discussion topics included the methodological quality of existing studies, evaluation of the evidence for causal effects of short interpregnancy intervals on adverse perinatal and maternal health outcomes, good practices for future research, and identification of research gaps and priorities for future work., Conclusions: This report provides an overview of the presentations, discussions, and conclusions from the expert work group meeting., (© 2018 The Authors. Paediatric and Perinatal Epidemiology Published by John Wiley & Sons Ltd.)

Background: Meta-analyses of observational studies have shown that women with a shorter interpregnancy interval (the time from delivery to start of a subsequent pregnancy) are more likely to experience adverse pregnancy outcomes, such as preterm delivery or small for gestational age birth, than women who space their births further apart. However, the studies used to inform these estimates have methodological shortcomings., Methods: In this commentary, we summarise the discussions of an expert workgroup describing good practices for the design, analysis, and interpretation of observational studies of interpregnancy interval and adverse perinatal health outcomes., Results: We argue that inferences drawn from research in this field will be improved by careful attention to elements such as: (a) refining the research question to clarify whether the goal is to estimate a causal effect vs describe patterns of association; (b) using directed acyclic graphs to represent potential causal networks and guide the analytic plan of studies seeking to estimate causal effects; (c) assessing how miscarriages and pregnancy terminations may have influenced interpregnancy interval classifications; (d) specifying how key factors such as previous pregnancy loss, pregnancy intention, and maternal socio-economic position will be considered; and (e) examining if the association between interpregnancy interval and perinatal outcome differs by factors such as maternal age., Conclusion: This commentary outlines the discussions of this recent expert workgroup, and describes several suggested principles for study design and analysis that could mitigate many potential sources of bias., (© 2018 The Authors. Paediatric and Perinatal Epidemiology Published by John Wiley & Sons Ltd.)

Context: The objective of this systematic review was to update a prior review and summarize the evidence (newly identified and cumulative) on the impact of contraceptive counseling provided in clinical settings., Evidence Acquisition: Multiple databases, including PubMed, were searched during 2016-2017 for articles published from March 1, 2011, to November 30, 2016., Evidence Synthesis: The search strategy identified 24,953 articles; ten studies met inclusion criteria. Two of three new studies that examined contraceptive counseling interventions (i.e., enhanced models to standard of care) among adolescents and young adults found a statistically significant positive impact on at least one outcome of interest. Five of seven new studies that examined contraceptive counseling, in general, or specific counseling interventions or aspects of counseling (e.g., personalization) among adults or mixed populations (adults and adolescents) found a statistically significant positive impact on at least one outcome of interest. In combination with the initial review, six of nine studies among adolescents and young adults and 16 of 23 studies among adults or mixed populations found a statistically significant positive impact of counseling on at least one outcome of interest., Conclusions: Overall, evidence supports the utility of contraceptive counseling, in general, and specific interventions or aspects of counseling. Promising components of contraceptive counseling were identified. The following would strengthen the evidence base: improved documentation of counseling content and processes, increased attention to the relationships between client experiences and behavioral outcomes, and examining the comparative effectiveness of different counseling approaches to identify those that are most effective., Theme Information: This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services., (Published by Elsevier Inc.)

Context: Community education and engagement are important for informing family planning projects. The objective of this study was to update two prior systematic reviews assessing the impact of community education and engagement interventions on family planning outcomes., Evidence Acquisition: Sixteen electronic databases were searched for studies relevant to a priori determined inclusion/exclusion criteria in high development settings, published from March 2011 through April 2016, updating two reviews that included studies from 1985 through February 2011., Evidence Synthesis: Nine relevant studies were included in this updated review related to community education, in addition to 17 from the prior review. No new community engagement studies met inclusion criteria, as occurred in the prior review. Of new studies, community education modalities included mass media, print/mail, web-based, text messaging, and interpersonal interventions. One study on mass media intervention demonstrated a positive impact on reducing teen and unintended pregnancies. Three of four studies on interpersonal interventions demonstrated positive impacts on medium-term family planning outcomes, such as contraception and condom use. Three new studies demonstrated mostly positive, but inconsistent, results on short-term family planning outcomes., Conclusions: Findings from this systematic review update are in line with a previous review showing the positive impact of community education using traditional modalities on short-term family planning outcomes, identifying additional impacts on long-term outcomes, and highlighting new evidence for education using modern modalities, such as text messaging and web-based education. More research is necessary to provide a stronger evidence base for directing community education and engagement efforts in family planning contexts., Theme Information: This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services., (Copyright © 2018. Published by Elsevier Inc.)

Context: Educational interventions can help individuals increase their knowledge of available contraceptive methods, enabling them to make informed decisions and use contraception correctly. This review updates a previous review of contraceptive education., Evidence Acquisition: Multiple databases were searched for articles published March 2011-November 2016. Primary outcomes were knowledge, participation in and satisfaction/comfort with decision making, attitudes toward contraception, and selection of more effective methods. Secondary outcomes included contraceptive behaviors and pregnancy. Excluded articles described interventions that had no comparison group, could not be conducted feasibly in a clinic setting, or were conducted outside the U.S. or similar country., Evidence Synthesis: A total of 24,953 articles were identified. Combined with the original review, 37 articles met inclusion criteria and described 31 studies implementing a range of educational approaches (interactive tools, written materials, audio/videotapes, and text messages), with and without healthcare provider feedback, for a total of 36 independent interventions. Of the 31 interventions for which knowledge was assessed, 28 had a positive effect. Fewer were assessed for their effect on attitudes toward contraception, selection of more effective methods, contraceptive behaviors, or pregnancy-although increased knowledge was found to mediate additional outcomes (positive attitudes toward contraception and contraceptive continuation)., Conclusions: This systematic review is consistent with evidence from the broader healthcare field in suggesting that a range of interventions can increase knowledge. Future studies should assess what aspects are most effective, the benefits of including provider feedback, and the extent to which educational interventions can facilitate behavior change and attainment of reproductive health goals., Theme Information: This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services., (Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Context: The purpose of this paper is to synthesize and evaluate the evidence on the effectiveness of repeat teen pregnancy prevention programs offered in clinical settings., Evidence Acquisition: Multiple databases were searched for peer-reviewed articles published from January 1985 to April 2016 that included key terms related to adolescent reproductive health services. Analysis of these studies occurred in 2017. Studies were excluded if they focused solely on sexually transmitted disease/HIV prevention services, or occurred outside of a clinic setting or the U.S., Canada, Europe, Australia, or New Zealand. Inclusion and exclusion criteria further narrowed the studies to those that included information on at least one short-term (e.g., increased knowledge); medium-term (e.g., increased contraceptive use); or long-term (e.g., decreased repeat teen pregnancy) outcome, or identified contextual barriers or facilitators for providing adolescent-focused family planning services. Standardized abstraction methods and tools were used to synthesize the evidence and assess its quality. Only studies of clinic-based programs focused on repeat teen pregnancy prevention were included in this review., Evidence Synthesis: The search strategy identified 27,104 citations, 940 underwent full-text review, and 120 met the adolescent-focused family planning services inclusion criteria. Only five papers described clinic-based programs focused on repeat teen pregnancy prevention. Four studies found positive (n=2) or null (n=2) effects on repeat teen pregnancy prevention; an additional study described facilitators for helping teen mothers remain linked to services., Conclusions: This review identified clinic-based repeat teen pregnancy prevention programs and few positively affect factors that may reduce repeat teen pregnancy. Access to immediate postpartum contraception or home visiting programs may be opportunities to meet adolescents where they are and reduce repeat teen pregnancy., Theme Information: This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services., (Copyright © 2018. Published by Elsevier Inc.)

Context: Providers can help clients achieve their personal reproductive goals by providing high-quality, client-centered contraceptive counseling. Given the individualized nature of contraceptive decision making, provider attention to clients' preferences for counseling interactions can enhance client centeredness. The objective of this systematic review was to summarize the evidence on what preferences clients have for the contraceptive counseling they receive., Evidence Acquisition: This systematic review is part of an update to a prior review series to inform contraceptive counseling in clinical settings. Sixteen electronic bibliographic databases were searched for studies related to client preferences for contraceptive counseling published in the U.S. or similar settings from March 2011 through November 2016. Because studies on client preferences were not included in the prior review series, a limited search was conducted for earlier research published from October 1992 through February 2011., Evidence Synthesis: In total, 26 articles met inclusion criteria, including 17 from the search of literature published March 2011 or later and nine from the search of literature from October 1992 through February 2011. Nineteen articles included results about client preferences for information received during counseling, 13 articles included results about preferences for the decision-making process, 13 articles included results about preferences for the relationship between providers and clients, and 11 articles included results about preferences for the context in which contraceptive counseling is delivered., Conclusions: Evidence from the mostly small, qualitative studies included in this review describes preferences for the contraceptive counseling interaction. Provider attention to these preferences may improve the quality of family planning care; future research is needed to explore interventions designed to meet preferences., Theme Information: This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The relationship between unintended pregnancy and interpregnancy interval (IPI) across maternal age is not clear., Methods: Using data from the National Survey of Family Growth, we estimated the percentages of pregnancies that were unintended among IPI groups (<6, 6-11, 12-17, 18-23, 24+ months) by maternal age at last live birth (15-19, 20-24, 25-29, 30-44 years)., Results: Approximately 40% of pregnancies were unintended and 36% followed an IPI<18 months. Within each maternal age group, the percentage of pregnancies that were unintended decreased as IPI increased., Conclusion: Unintended pregnancies are associated with shorter IPI across the reproductive age spectrum., (Published by Elsevier Inc.)

Rates of short-interval pregnancies that result in unintended pregnancies remain high in the United States and contribute to adverse reproductive health outcomes. Long-acting reversible contraception methods have annual failure rates of <1%, compared with 9% for oral contraceptive pills, and are an effective strategy to reduce unintended pregnancies. To increase access to long-acting reversible contraception in the immediate postpartum period, several State Medicaid programs, which include those in Iowa and Louisiana, recently established reimbursement policies to remove the barriers to reimbursement of immediate postpartum long-acting reversible contraception insertion. We used a mixed-methods approach to analyze 2013-2015 linked Medicaid and vital records data from both Iowa and Louisiana and to describe trends in immediate postpartum long-acting reversible contraception provision 1 year before and after the Medicaid reimbursement policy change. We also used data from key informant interviews with state program staff to understand how provider champions affected policy uptake. We found that the monthly average for the number of insertions in Iowa increased from 4.6 per month before the policy to 6.6 per month after the policy; in Louisiana, the average number of insertions increased from 2.6 per month before the policy to 45.2 per month. In both states, the majority of insertions occurred at 1 academic/teaching hospital. In Louisiana, the additional increase may be due to the engagement of a provider champion who worked at both the state and facility level. Recruiting, training, engaging, and supporting provider champions, as facilitators, with influence at state and facility levels, is an important component of a multipart strategy for increasing successful implementation of state-level Medicaid payment reform policies that allow reimbursement for immediate postpartum long-acting reversible contraception insertions., (Published by Elsevier Inc.)

Objective: Lesbian, gay, bisexual, transgender, queer/questioning, intersex and asexual (LGBTQIA) individuals have unique sexual and reproductive health needs; however, facilitators and barriers to optimal care are largely understudied. The objective of this study was to synthesize findings from a systematic review of the literature regarding the provision of quality family planning services to LGBTQIA clients to inform clinical and research strategies., Study Design: Sixteen electronic bibliographic databases (e.g., PubMed, PSYCinfo) were searched to identify articles published from January 1985 to April 2016 relevant to the analytic framework., Results: The search parameters identified 7193 abstracts; 19 descriptive studies met inclusion criteria. No studies assessed the impact of an intervention serving LGBTQIA clients on client experience, behavior or health outcomes. Two included studies focused on the perspectives of health care providers towards LGBTQIA clients. Of the 17 studies that documented client perspectives, 12 elucidated factors facilitating a client's ability to enter into care, and 13 examined client experience during care. Facilitators to care included access to a welcoming environment, clinicians knowledgeable about LGBTQIA needs and medical confidentiality., Conclusions: This systematic review found a paucity of evidence on provision of quality family planning services to LGBTQIA clients. However, multiple contextual facilitators and barriers to family planning service provision were identified. Further research is needed to assess interventions designed to assist LGBTQIA clients in clinical settings, and to gain a better understanding of effective education for providers, needs of specific subgroups (e.g., asexual individuals) and the role of the client's partner during receipt of care., (Published by Elsevier Inc.)

LGBT clients have unique healthcare needs but experience a wide range of quality in the care that they receive. This study provides a summary of clinical guideline recommendations related to the provision of primary care and family planning services for LGBT clients. In addition, we identify gaps in current guidelines, and inform future recommendations and guidance for clinical practice and research. PubMed, Cochrane, and Agency for Healthcare Research and Quality electronic bibliographic databases, and relevant professional organizations' websites, were searched to identify clinical guidelines related to the provision of primary care and family planning services for LGBT clients. Information obtained from a technical expert panel was used to inform the review. Clinical guidelines meeting the inclusion criteria were assessed to determine their alignment with Institute of Medicine (IOM) standards for the development of clinical practice guidelines and content relevant to the identified themes. The search parameters identified 2,006 clinical practice guidelines. Seventeen clinical guidelines met the inclusion criteria. Two of the guidelines met all eight IOM criteria. However, many recommendations were consistent regarding provision of services to LGBT clients within the following themes: clinic environment, provider cultural sensitivity and awareness, communication, confidentiality, coordination of care, general clinical principles, mental health considerations, and reproductive health. Guidelines for the primary and family planning care of LGBT clients are evolving. The themes identified in this review may guide professional organizations during guideline development, clinicians when providing care, and researchers conducting LGBT-related studies.

Context: The United Nations Sustainable Development Goals (SDGs) seek to achieve health equity, and they apply to all countries. SDG contraceptive use estimates for the United States are needed to contextualize U.S. performance in relation to that of other countries., Methods: Data from the 2011-2013 and 2013-2015 waves of the National Survey of Family Growth were used to calculate three SDG indicators of contraceptive use for U.S. women aged 15-44: contraceptive prevalence, unmet need for family planning and demand for family planning satisfied by modern methods. These measures were calculated separately for married or cohabiting women and for unmarried, sexually active women; differences by sociodemographic characteristics were assessed using t tests from logistic regression analysis. Estimates for married women were compared with 2010-2015 estimates from 94 other countries, most of which were low- or middle-income., Results: For married or cohabiting women, U.S. estimates for contraceptive prevalence, unmet need and demand satisfied by modern methods were 74%, 9% and 80%, respectively; for unmarried, sexually active women, they were 85%, 11% and 82%, respectively. Estimates varied by sociodemographic characteristics, particularly among married or cohabiting women. Five countries performed better than the United States on contraceptive prevalence, 12 on unmet need and four on both measures; seven performed better on demand satisfied by modern methods., Conclusions: There is a need to continue efforts to expand access to contraceptive care in the United States, and to monitor the SDG indicators so that improvement can be tracked over time., (Copyright © 2017 by the Guttmacher Institute.)

Objectives To describe statewide SMM trends in Iowa from 2009 to 2014 and identify maternal characteristics associated with SMM, overall and by age group. Methods We used 2009-2014 linked Iowa birth certificate and hospital discharge data to calculate SMM based on a 25-condition definition and 24-condition definition. The 24-condition definition parallels the 25-condition definition, but excludes blood transfusions. We calculated SMM rates for all delivery hospitalizations (N = 196,788) using ICD-9-CM diagnosis and procedure codes. We used log-binomial regression to assess the association of SMM with maternal characteristics, overall and stratified by age groupings. Results In contrast to national rates, Iowa's 25-condition SMM rate decreased from 2009 to 2014. Based on the 25-condition definition, SMM rates were significantly higher among women <20 years and >34 years compared to women 25-34 years. Blood transfusion was the most prevalent indicator, with hysterectomy and disseminated intravascular coagulation (DIC) among the top five conditions. Based on the 24-condition definition, younger women had the lowest SMM rates and older women had the highest SMM rates. SMM rates were also significantly higher among racial/ethnic minorities compared to non-Hispanic white women. Payer was the only risk factor differentially associated with SMM across age groups. First trimester prenatal care initiation was protective for SMM in all models. Conclusions High rates of blood transfusion, hysterectomy, and DIC indicate a need to focus on reducing hemorrhage in Iowa. Both younger and older women and racial/ethnic minorities are identified as high risk groups for SMM that may benefit from special consideration and focus.

Objectives: To assess feasibility of calculating clinical performance measures for contraceptive care for National Quality Forum submission: the percentage of women aged 15-44 years provided the following: (1) a most or moderately effective contraceptive method (MME) and (2) a long-acting reversible contraceptive (LARC) method., Methods: We used 2013 Iowa Department of Public Health (IDPH) Title X and Iowa Medicaid data. We stratified Title X data by age and Medicaid data by age and benefit type (family planning waiver (FPW) vs. general Medicaid), and examined variation by residence, public health region and health plan based on program interest., Findings: Among women attending IDPH Title X clinics in 2013 (N=11,584), 86% of women aged 15-20years and 83% of women aged 21-44years were provided MME; and 20% of women aged 15-20years and 20% of women aged 21-44years were provided LARC. Estimates varied across Title X subrecipient agencies, which receive federal funds from IDPH. Among Medicaid FPW clients (N=30,013), 79% of women aged 15-20years and 73% of women aged 21-44years were provided MME; and 12% of women aged 15-20years and 11% of women aged 21-44years were provided LARC. Among general Medicaid clients (N=14,737), 40% of women aged 15-20years and 28% of women aged 21-44years were provided MME; and 5% of women aged 15-20years and 5% of women aged 21-44years were provided LARC., Conclusion: A high percentage of IDPH Title X and FPW clients were provided an MME method. No reporting entity had a LARC percentage less than 1%-2%., Implications: Measure calculation using Title X and Medicaid data is feasible and can potentially be used to identify ways to increase access to contraceptive methods., (Published by Elsevier Inc.)

We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Background: Timing of solid food introduction in infancy has been associated with several chronic diseases. To explore potential mechanisms, we investigated the relationship between timing of solid food introduction and F2-isoprostanes-a marker of oxidative stress., Methods: Urinary F2-isoprostanes were assessed in 336 healthy children aged less than 11.5 y with 1,266 clinic visits (mean = 3.8 visits per child) in the Diabetes Autoimmunity Study in the Young. We analyzed the association between F2-isoprostane concentrations and infant diet exposures using linear mixed models adjusted for age, age(2), HLA-DR3/4,DQB1*0302 genotype, first-degree relative with type 1 diabetes, maternal age, maternal education, sex, and exposure to in utero cigarette smoke., Results: Later solid food introduction was associated with lower F2-isoprostane concentrations in childhood (on average, 0.10 ng/mg per month of age at introduction; estimate: -0.10 (95% confidence interval (CI): -0.18, -0.02) P value = 0.02). Moreover, childhood F2-isoprostane concentrations were, on average, 0.24 ng/mg lower in individuals breastfed at solid food introduction (estimate: -0.24 (95% CI: -0.47, -0.01) P value = 0.04) compared with those who were not. Associations remained significant after limiting analyses to F2-isoprostanes after 2 y of age., Conclusion: Our results suggest a long-term protective effect of later solid food introduction and breastfeeding at solid food introduction against increased F2-isoprostane concentrations throughout childhood.

Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

Aims/hypotheses: We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY)., Methods: DAISY is following 2,547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)65, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children., Results: Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09, 0.55), while α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (pinteraction = 0.017), at FADS2 rs174570 (pinteraction = 0.016) and at FADS2 rs174583 (pinteraction = 0.045)., Conclusions/interpretation: The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically controlled fatty acid desaturation.

Context: Vitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk; however, these genes have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA). Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases., Objective: The objective of the study was to explore the association between seven vitamin D metabolism gene single-nucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D., Design: The Diabetes Autoimmunity Study in the Young is a longitudinal, observational study., Setting: Newborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place in Denver, Colorado., Participants: A total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62 IA-positive children progressed to T1D., Main Outcome Measures: IA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures., Results: The risk of IA was associated with DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 [hazard ratio 1.36, 95% confidence interval 1.08-1.73 (for each additional minor allele) and hazard ratio 0.59, 95% confidence interval 0.39-0.89 (for A/G compared with the A/A genotype), respectively]. None of the vitamin D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were significantly associated with 25-hydroxyvitamin D levels., Conclusions: DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity, the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.

Previously, we examined 20 non-HLA SNPs for association with islet autoimmunity (IA) and/or progression to type 1 diabetes (T1D). Our objective was to investigate fourteen additional non-HLA T1D candidate SNPs for stage- and age-related heterogeneity in the etiology of T1D. Of 1634 non-Hispanic white DAISY children genotyped, 132 developed IA (positive for GAD, insulin, or IA-2 autoantibodies at two or more consecutive visits); 50 IA positive children progressed to T1D. Cox regression was used to analyze risk of IA and progression to T1D in IA positive children. Restricted cubic splines were used to model SNPs when there was evidence that risk was not constant with age. C1QTNF6 (rs229541) predicted increased IA risk (HR: 1.57, CI: 1.20-2.05) but not progression to T1D (HR: 1.13, CI: 0.75-1.71). SNP (rs10517086) appears to exhibit an age-related effect on risk of IA, with increased risk before age 2 years (age 2 HR: 1.67, CI: 1.08-2.56) but not older ages (age 4 HR: 0.84, CI: 0.43-1.62). C1QTNF6 (rs229541), SNP (rs10517086), and UBASH3A (rs3788013) were associated with development of T1D. This prospective investigation of non-HLA T1D candidate loci shows that some SNPs may exhibit stage- and age-related heterogeneity in the etiology of T1D.