Publications by authors named "Leslie V Farland"

66 Publications

SARS-CoV-2 infection and subsequent changes in the menstrual cycle among participants in the Arizona CoVHORT study.

Am J Obstet Gynecol 2021 Sep 20. Epub 2021 Sep 20.

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, The University of Arizona, Tucson, AZ; The University of Arizona Cancer Center, Tucson, AZ; Department of Obstetrics and Gynecology, College of Medicine-Tucson, The University of Arizona, Tucson, AZ.

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http://dx.doi.org/10.1016/j.ajog.2021.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452349PMC
September 2021

Age and Cohort Trends of Malignant Melanoma in the United States.

Cancers (Basel) 2021 Jul 31;13(15). Epub 2021 Jul 31.

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA.

The incidence of malignant melanoma in the United States is increasing, possibly due to changes in ultraviolet radiation (UVR) exposure due to lifestyle or increased awareness and diagnosis of melanoma. To determine if more recent birth cohorts experience higher rates of melanoma as they age, we examined age and birth cohort trends in the United States stratified by anatomic site and cancer type (in situ vs. malignant) of the melanoma diagnosed from 1975-2017. Poisson regression of cutaneous melanoma cases per population for 1975-2017 from the Surveillance, Epidemiology, and End Results (SEER) cancer registries was used to estimate age adjusted incidence for five-year birth cohorts restricted to Whites, ages 15-84. The rate of melanoma incidence across birth cohorts varies by anatomic site and sex. Melanomas at all anatomic sites continue to increase, except for head and neck melanomas in men. Much of the increase in malignant melanoma is driven by cases of thin (<1.5 mm) lesions. While increased skin exams may contribute to the increased incidence of in situ and thin melanoma observed across birth cohorts, the shifts in anatomic site of highest melanoma incidence across birth cohorts suggest changes in UVR exposure may also play a role.
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http://dx.doi.org/10.3390/cancers13153866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345588PMC
July 2021

Post-acute sequelae of COVID-19 in a non-hospitalized cohort: Results from the Arizona CoVHORT.

PLoS One 2021 4;16(8):e0254347. Epub 2021 Aug 4.

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, The University of Arizona, Tucson, AZ, United States of America.

Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as long COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of PASC, defined as experiencing at least one symptom 30 days or longer, and prevalence of individual symptoms. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30-250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95% confidence interval: 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress/anxiety (30.8%). The median number of symptoms was 3 (range 1-20). Amongst 157 participants with longer follow-up (≥60 days), PASC prevalence was 77.1%.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336814PMC
August 2021

Influence of Placental Abnormalities and Pregnancy-Induced Hypertension in Prematurity Associated with Various Assisted Reproductive Technology Techniques.

J Clin Med 2021 Apr 14;10(8). Epub 2021 Apr 14.

Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.

Objective: Assisted reproductive technology (ART)-treated women exhibit increased risk of premature delivery compared to fertile women. We evaluated whether ART treatment modalities increase prematurity and whether placental abnormalities and pregnancy-induced hypertensive (PIH) disorders mediate these risks.

Method(s): This retrospective study of ART-treated and fertile deliveries (2004-2017) used an ART-cycle database linked to Massachusetts birth certificates and hospital discharges. Outcomes of late preterm birth (LPTB: 34-36 weeks gestation) and early preterm birth (EPTB: <34 weeks gestation) were compared with term deliveries (≥37 weeks gestation) in ART-treated (linked to the ART database) and fertile (no indicators of infertility or ART) deliveries. ART treatments with autologous oocyte, donor oocyte, fresh or frozen embryo transfer (FET), intracytoplasmic sperm injection (ICSI) and no-ICSI were separately compared to the fertile group. Adjusted odds ratios (AOR) were calculated with multivariable logistic regression: placental abnormalities or PIH were quantified in the pathway as mediators.

Results: There were 218,320 deliveries: 204,438 fertile and 13,882 ART-treated. All treatment types increased prematurity (AOR 1.31-1.58, LPTB; AOR 1.34-1.48, EPTB). Placental abnormalities mediated in approximately 22% and 38% of the association with LPTB and EPTB, respectively. PIH mediated 25% and 33% of the association with LPTB and EPTB in FET and donor oocyte cycles, more than other treatments (<10% LPTB and <13% EPTB).

Conclusions: ART-treatment and all ART modalities increased LPTB and EPTB when compared with fertile deliveries. Placental abnormalities modestly mediated associations approximately equally, while PIH was a stronger mediator in FET and donor oocyte cycles. Reasons for differences require exploration.
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http://dx.doi.org/10.3390/jcm10081681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070757PMC
April 2021

Self-reported infertility diagnoses and treatment history approximately 20 years after fertility treatment initiation.

Fertil Res Pract 2021 Mar 12;7(1). Epub 2021 Mar 12.

Mel and Enid Zuckerman College of Public Health, University of Arizona, 1295 N. Martin Avenue, Tucson, AZ, 85724, USA.

Background: Infertility history may have important implications for clinical practice and scientific discovery. Previous research on the validity of self-reported infertility measurements has been limited in scope and duration (< 5 years). In this study, we validated self-reported infertility history measures 15-23 years after fertility treatment initiation among women who utilized assisted reproductive technology (ART).

Methods: Women who received ART treatments from three Boston infertility clinics and who enrolled in a prior study (1994-2003) were re-contacted in 2018 for the AfteR Treatment Follow-up Study (ART-FS). Infertility history was collected from clinical records and two self-report questionnaires (at ART initiation and at ART-FS enrollment). Treatment history included specific details (fresh or frozen embryo transfers, number of cycles) and treatment recall prior to ART initiation. Self-reported infertility diagnoses included polycystic ovary syndrome (PCOS), endometriosis, uterine factor infertility, tubal factor infertility, diminished ovarian reserve/advanced maternal age, male factor infertility, and other/unknown. We compared self-reported measures from 2018 to self-reported and clinical data from prior study initiation, using Cohen's kappa, sensitivity, specificity, and 95% confidence intervals.

Results: Of 2644 women we attempted to recontact, 808 completed the ART-FS, with an average follow-up of 19.6 years (standard deviation: 2.7). Recall of fertility treatment usage had moderate sensitivity (IVF = 0.85, Clomiphene/Gonadotropin = 0.81) but low specificity across different infertility treatment modalities (IVF = 0.63, Clomiphene/Gonadotropin = 0.55). Specific IVF details had low to moderate validity and reliability with clinical records. Reliability of recalled infertility diagnosis was higher when compared to self-report at ART initiation (PCOS K = 0.66, Endometriosis K = 0.76, Tubal K = 0.73) than when compared to clinical records (PCOS K = 0.31, Endometriosis K = 0.48, Tubal K = 0.62) and varied by diagnosis.

Conclusions: The ability of women to recall specific IVF treatment details was moderately accurate and recall of self-reported infertility diagnosis varied by diagnosis and measurement method.
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http://dx.doi.org/10.1186/s40738-021-00099-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953690PMC
March 2021

Design of the Arizona CoVHORT: A Population-Based COVID-19 Cohort.

Front Public Health 2021 10;9:620060. Epub 2021 Feb 10.

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, The University of Arizona, Tucson, AZ, United States.

This study is a prospective, population-based cohort of individuals with a history of SARS-CoV-2 infection and those without past infection through multiple recruitment sources. The main study goal is to track health status over time, within the diverse populations of Arizona and to identify the long-term consequences of COVID-19 on health and well-being. A total of 2,881 study participants (16.2% with a confirmed SARS-CoV-2 infection) have been enrolled as of December 22, 2020, with a target enrollment of 10,000 participants and a planned follow-up of at least 2 years. This manuscript describes a scalable study design that utilizes a wide range of recruitment sources, leveraging electronic data collection to capture and link longitudinal participant data on the current and emerging issues associated with the COVID-19 pandemic. The cohort is built within a collaborative infrastructure that includes new and established partnerships with multiple stakeholders, including the state's public universities, local health departments, tribes, and tribal organizations. Challenges remain for ensuring recruitment of diverse participants and participant retention, although the electronic data management system and timing of participant contact can help to mitigate these problems.
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http://dx.doi.org/10.3389/fpubh.2021.620060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902773PMC
March 2021

Optimizing the control group for evaluating ART outcomes: can outpatient claims data yield a better control group?

J Assist Reprod Genet 2021 May 19;38(5):1089-1100. Epub 2021 Feb 19.

Massachusetts Department of Public Health, Bureau of Family Health and Nutrition, Boston, MA, USA.

Purpose: We previously developed a subfertile comparison group with which to compare outcomes of assisted reproductive technology (ART) treatment. In this study, we evaluated whether insurance claims data in the Massachusetts All Payers Claims Database (APCD) defined a more appropriate comparison group.

Methods: We used Massachusetts vital records of women who delivered between 2013 and 2017 on whom APCD data were available. ART deliveries were those linked to a national ART database. Deliveries were subfertile if fertility treatment was marked on the birth certificate, had prior hospitalization with ICD code for infertility, or prior fertility treatment. An infertile group included women with an APCD outpatient or inpatient ICD 9/10 infertility code prior to delivery. Fertile deliveries were none of the above. Demographics, health risks, and obstetric outcomes were compared among groups. Multivariable generalized estimating equations were used to calculate adjusted relative risk (aRR) and 95% confidence intervals (CI).

Results: There were 70,726 fertile, 4,763 subfertile, 11,970 infertile, and 7,689 ART-treated deliveries. Only 3,297 deliveries were identified as both subfertile and infertile. Both subfertile and infertile were older, and had more education, chronic hypertension, and diabetes than the fertile group and less than the ART-treated group. Prematurity (aRR = 1.15-1.17) and birthweight (aRR = 1.10-1.21) were increased in all groups compared with the fertile group.

Conclusion: Although the APCD allowed identification of more women than the previously defined subfertile categorization and allowed us to remove previously unidentified infertile women from the fertile group, it is not clear that it offered a clinically significantly improved comparison group.
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http://dx.doi.org/10.1007/s10815-021-02111-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190220PMC
May 2021

Co-occurrence of immune-mediated conditions and endometriosis among adolescents and adult women.

Am J Reprod Immunol 2021 07 25;86(1):e13404. Epub 2021 Feb 25.

Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Problem: Associations between immune dysfunction conditions (eg, systemic lupus erythematous, rheumatoid arthritis) and endometriosis have been observed in adult women, but not assessed among a younger population. We investigated the association between immune-mediated conditions and endometriosis among young women.

Method Of Study: This cross-sectional analysis in the Women's Health Study: From Adolescence to Adulthood included 551 participants with surgically diagnosed endometriosis (median age=19) and 652 controls without endometriosis (median age=24). Participants completed an expanded Endometriosis Phenome and Biobanking Harmonization Project questionnaire. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to investigate the associations between autoimmune/inflammatory, atopic, chronic pain/fatigue, and endocrine disorders with endometriosis, adjusting for confounders.

Results: Participants with any autoimmune and/or inflammatory condition had an increased odds of co-occurring endometriosis (OR: 1.87; CI: 0.92-3.80), as did participants with allergies (OR: 1.76; CI: 1.32-2.36), asthma (OR: 1.35; CI: 0.97-1.88), chronic fatigue syndrome and/or fibromyalgia (OR: 5.81; CI: 1.89-17.9), or previous mononucleosis (OR: 1.75; CI: 1.14-2.68). Odds of endometriosis were lower among participants with eczema (OR: 0.68; CI: 0.44-1.04). We observed a positive trend between the number of immune-mediated conditions and the odds of endometriosis (p-trend=0.0002). Endocrine disorders were not associated with endometriosis.

Conclusions: Among this population of adolescents and adult women, endometriosis was more likely among participants with autoimmune and/or inflammatory diseases, allergies, asthma, previous mononucleosis infection, and chronic fatigue and/or fibromyalgia. We observed that an increasing number of immune-mediated conditions were positively associated with endometriosis risk. It is important for clinicians who care for adolescents and women with these conditions to consider endometriosis as a comorbidity.
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http://dx.doi.org/10.1111/aji.13404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243788PMC
July 2021

Long-term Health Consequences of Endometriosis - Pathways and Mediation by Treatment.

Curr Obstet Gynecol Rep 2020 Sep 29;9(3):79-88. Epub 2020 May 29.

Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose Of Review: The purpose of this review is to discuss the most up to date research on endometriosis and chronic disease risk, highlighting the role treatments for endometriosis may play in these associations.

Recent Findings: Previous studies have shown a consistent association between endometriosis and risk for epithelial ovarian cancer but the association with other cancers is less clear. Current research indicates that endometriosis may in be associated with risk of systemic lupus erythematosus, and potentially other autoimmune diseases. Limited evidence is also present for the association between endometriosis and cardiovascular disease and related conditions (e.g,. hypertension, hypercholesterolemia). A potential explanation for a portion of the increased risk of chronic diseases among women with endometriosis may relate to treatments for endometriosis impacting these outcomes.

Summary: Given the prevalence of endometriosis, understanding the relation between endometriosis and other chronic diseases has the potential to impact the health of many women. However, few high-quality studies with limited biases and adequate follow-up currently exist. Future multi-disciplinary research in prospective cohorts, with ample follow-up time, and detailed information on endometriosis characteristics and treatment is critical to advancing our understanding of this disease and its consequences.
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http://dx.doi.org/10.1007/s13669-020-00287-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864355PMC
September 2020

Recreational and residential sun exposure and risk of endometriosis: a prospective cohort study.

Hum Reprod 2021 01;36(1):199-210

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Study Question: Is recreational and residential sun exposure associated with risk of endometriosis?

Summary Answer: Tanning bed use in early adulthood, sunscreen use and history of sunburns were associated with a greater risk of endometriosis; however, higher residential UV exposure was associated with a lower endometriosis risk.

What Is Known Already: Previous research has reported an association between endometriosis and skin cancer, with evidence of shared risk factors between the two diseases. We investigated the potential associations between ultraviolet radiation and endometriosis risk.

Study Design, Size, Duration: The Nurses' Health Study II is a prospective cohort of 116 429 female US nurses aged 25-42 years at enrolment in 1989. Participants completed self-administered biennial questionnaires through June 2015.

Participants/materials, Settings, Methods: We investigated self-reported measures of recreational sun-exposure and geocoded residential UV exposure in childhood and adulthood in relation to risk of laparoscopically confirmed endometriosis among premenopausal white women. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CIs.

Main Results And The Role Of Chance: During follow-up, 4791 incident cases of laparoscopically confirmed endometriosis were reported among 1 252  248 person-years. Tanning bed use during high school/college (≥6 times per year vs. never use: HR = 1.19, 95% CI = 1.01-1.40; Ptrend = 0.04) and at ages 25-35 (HR = 1.24, 95% CI = 1.12-1.39; Ptrend ≤ 0.0001), number of sunburns during adolescence (Ptrend = 0.03) and percentage of time using sunscreen in adulthood (Ptrend = 0.002) were positively associated with risk of endometriosis. In contrast, residential UV level at birth (highest vs. lowest quintile: HR = 0.81, 95% CI = 0.72-0.92; Ptrend = 0.0001), at age 15 (HR = 0.79, 95% CI = 0.70-0.88; Ptrend ≤ 0.0001) and at age 30 (HR = 0.90, 95% CI = 0.82-0.99; Ptrend = 0.21) were associated with a decreased risk of endometriosis.

Limitations, Reasons For Caution: Self-reported endometriosis diagnosis may be prone to misclassification; however, we restricted our definition to laparoscopically confirmed endometriosis, which has been shown to have high validity compared to medical records.

Wider Implications Of The Findings: Our results suggest that tanning bed use in early adulthood increases endometriosis risk, potentially through a harmful effect of ultraviolet A wavelengths, and that residential UV exposure reduces risk, possibly via optimal vitamin D synthesis. These findings should be investigated further to enhance our understanding of endometriosis aetiology.

Study Funding/competing Interest(s): This project was supported by NICHD grants HD48544 and HD52473, HD57210, NIH grant CA50385, CA176726. M.K. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. H.R.H. is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). The authors have nothing to disclose.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801789PMC
January 2021

A prospective study of endometriosis and risk of type 2 diabetes.

Diabetologia 2021 Mar 5;64(3):552-560. Epub 2021 Jan 5.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Aims/hypothesis: The objective of this study was to investigate the association between laparoscopically confirmed endometriosis and risk of type 2 diabetes.

Methods: We used data from the Nurses' Health Study II, a prospective cohort of female nurses followed for >25 years (N = 112,037). We used Cox proportional hazards models to estimate the HRs and 95% CIs of incident, confirmed type 2 diabetes (n = 8496 participants) adjusted a priori for confounding factors. We additionally investigated differences in the relationship between endometriosis and type 2 diabetes by age (<50 or ≥50 years), BMI (<30 or ≥30 kg/m), infertility history, menopausal status and history of gestational diabetes mellitus (GDM; restricted to parous women).

Results: We saw no association between laparoscopically confirmed endometriosis and risk of type 2 diabetes in multivariable confounder-adjusted models (HR 1.06 [95% CI 0.98, 1.13]) or models accounting for potential mediating factors (HR 0.94 [95% CI 0.87, 1.00]). However, we observed modest differences in the association between endometriosis and type 2 diabetes by BMI group, history of infertility and history of GDM. Among non-obese women (HR 1.17 [95% CI 1.02, 1.35]), women who never experienced infertility (HR 1.14 [95% CI 1.04, 1.25]) and women who never experienced GDM (HR 1.11 [95% CI 1.01, 1.22]), endometriosis was associated with greater risk of type 2 diabetes.

Conclusions/interpretation: Overall, women with endometriosis were not at increased risk of type 2 diabetes. However, among subgroups at low risk for type 2 diabetes (i.e. non-obese women and women with no prior history of infertility or GDM), endometriosis was associated with a modest increased risk of type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-020-05347-6DOI Listing
March 2021

The risk of birth defects with conception by ART.

Hum Reprod 2021 01;36(1):116-129

Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Study Question: What is the association between ART conception and treatment parameters and the risk of birth defects?

Summary Answer: Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively.

What Is Known Already: Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved.

Study Design, Size, Duration: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived.

Participants/materials, Setting, Methods: The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded.

Main Results And The Role Of Chance: A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017.

Limitations, Reasons For Caution: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility.

Wider Implications Of The Findings: The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study.

Study Funding/competing Interest(s): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa272DOI Listing
January 2021

Early-life cancer, infertility, and risk of adverse pregnancy outcomes: a registry linkage study in Massachusetts.

Cancer Causes Control 2021 Feb 27;32(2):169-180. Epub 2020 Nov 27.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Purpose: Investigate the relationship between history of cancer and adverse pregnancy outcomes according to subfertility/fertility treatment.

Methods: Deliveries (2004-2013) from Massachusetts (MA) Registry of Vital Records and Statistics were linked to MA assisted reproductive technology data, hospital discharge records, and Cancer Registry. The relative risks (RR) and 95% confidence intervals of adverse outcomes (gestational diabetes (GDM), gestational hypertension (GHTN), cesarean section (CS), low birth weight (LBW), small for gestational age (SGA), preterm birth (PTB), neonatal mortality, and prolonged neonatal hospital stay) were modeled with log-link and Poisson distribution generalized estimating equations. Differences by history of subfertility/fertility treatment were investigated with likelihood ratio tests.

Results: Among 662,630 deliveries, 2,983 had a history of cancer. Women with cancer history were not at greater risk of GDM, GHTN, or CS. However, infants born to women with prior cancer had higher risk of LBW (RR: 1.19 [1.07-1.32]), prolonged neonatal hospital stay (RR: 1.16 [1.01-1.34]), and PTB (RR: 1.19 [1.07-1.32]). We found clinically and statistically significant differences in the relationship between cancer history and SGA by subfertility/fertility treatment (p value, test for heterogeneity = 0.02); among deliveries with subfertility or fertility treatment, those with a history of cancer experienced a greater risk of SGA (RRsubfertile: 1.36 [1.02-1.83]).

Conclusions: Women with a history of cancer had greater risk of some adverse pregnancy outcomes; this relationship varied by subfertility and fertility treatment.
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http://dx.doi.org/10.1007/s10552-020-01371-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855547PMC
February 2021

Endometriosis and cancer: a systematic review and meta-analysis.

Hum Reprod Update 2021 Feb;27(2):393-420

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation.

Objective And Rationale: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians.

Search Methods: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.

Outcomes: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies.

Wider Implications: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.
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http://dx.doi.org/10.1093/humupd/dmaa045DOI Listing
February 2021

Sex differences in infant health following ART-treated, subfertile, and fertile deliveries.

J Assist Reprod Genet 2021 Jan 13;38(1):211-218. Epub 2020 Nov 13.

Department of Obstetrics and Gynecology and Pathology, Dartmouth-Hitchcock, Lebanon, NH, USA.

Purpose: Among infants following ART-treated, subfertile, and fertile deliveries to determine (1) the presence and magnitude of sex differences in health outcomes and (2) whether the presence of sex differences varied among maternal fertility groups.

Methods: Retrospective cohort analysis of infants born in Massachusetts (MA) in 2004-2013 who were conceived by ART. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System was linked to the Pregnancy to Early Life Longitudinal data system, which links birth certificates to hospital discharge records for MA mothers and infants. Included were singletons born via ART-treated, subfertile, and fertile deliveries. Multivariable logistic regression was used to model the association between infant sex and health outcomes, controlling for maternal demographic and health characteristics.

Results: A total of 16,034 ART-treated, 13,277 subfertile, and 620,375 fertile singleton live births were included. For all three groups, males had greater odds of being preterm (AOR range 1.15-1.2), having birth defects (AOR range 1.31-1.71), experiencing respiratory (AOR range 1.33-1.35) and neurologic (AOR range 1.24-1.3) conditions, and prolonged hospital stay (AOR range 1.19-1.25) compared to females. The interaction between maternal fertility group and infant sex for all infant outcomes was nonsignificant, denoting that the presence of sex differences among fertile, subfertile, and ART groups did not vary.

Conclusion: Sex differences in birth outcomes of infants following ART-treated, subfertile, and fertile deliveries exist but the magnitude of these differences does not vary among these maternal fertility groups.
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http://dx.doi.org/10.1007/s10815-020-02004-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822984PMC
January 2021

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Circulation 2021 Feb 9;143(5):410-423. Epub 2020 Nov 9.

Cardiology Division (M.C.H., J.P.P., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.

Methods: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.

Results: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; =0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; =0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; =0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; <0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; =0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; =0.005).

Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911856PMC
February 2021

The epidemiology of gynaecologic health: contemporary opportunities and challenges.

J Epidemiol Community Health 2020 Oct 27. Epub 2020 Oct 27.

Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

The field of reproductive epidemiology has primarily focused on reproductive outcomes and gynaecologic cancers. The study of non-cancerous, gynaecologic conditions (eg, uterine fibroids, endometriosis) has not received serious treatment in existing epidemiology textbooks and reproductive epidemiology curricula. Further, these conditions do not neatly fit into the other common subdisciplines within epidemiology (eg, infectious disease, cardiovascular, injury and occupational epidemiology and so on). In this commentary, we identify and illustrate three critical challenges to advancing the epidemiologic research of non-cancerous, gynaecologic conditions. With greater investment and a patient-centred approach, epidemiology can advance knowledge about this critical area of human welfare.
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http://dx.doi.org/10.1136/jech-2019-213149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095335PMC
October 2020

Seasonal variation, temperature, day length, and IVF outcomes from fresh cycles.

J Assist Reprod Genet 2020 Oct 13;37(10):2427-2433. Epub 2020 Aug 13.

Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Purpose: It is known that delivery rates from spontaneous conception vary according to season which may be due to cultural or environmental factors; however, conflicting data exist regarding whether outcomes from IVF are also seasonally dependent. The present study was designed to test the hypothesis that the season at oocyte retrieval is associated with livebirth after fresh transfer.

Methods: Dates of oocyte retrieval for all autologous cycles in our IVF program between January 2012 and December 2017 were categorized by season. Dates were linked to local temperature (min, max, average) and day length obtained from meteorological records. Average maximum temperature and day length were categorized into tertiles. Multivariable logistic regression, adjusted for age and quadratic age, were used to model odds (aOR) of implantation, clinical pregnancy, spontaneous abortion, and livebirth.

Results: Patient characteristics were similar across seasons. As expected, temperature and day length varied by season. When compared with cycles started during winter, there was no difference in the age-adjusted odds of livebirth for the other three seasons (spring: aOR: 0.97, 95% CI: 0.82-1.13; summer: aOR: 1.05, 0.90-1.23; fall: aOR: 0.98, 0.84-1.15). There was a positive linear trend between temperature and odds of implantation, and clinical pregnancy (p value, test for linear trend (implantation, p = 0.02; clinical pregnancy, p = 0.01)) but no association with livebirth for temperature or day length.

Conclusions: We found that season at oocyte retrieval was not associated with livebirth, contrary to patterns seen in naturally conceived populations. However, our data did suggest modestly higher odds of clinical pregnancy for retrievals in June and July, and that higher temperature at time of retrieval was associated with higher odds of clinical pregnancy but not livebirth.
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http://dx.doi.org/10.1007/s10815-020-01915-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550498PMC
October 2020

In utero and early life exposures in relation to endometriosis in adolescents and young adults.

Eur J Obstet Gynecol Reprod Biol 2020 Sep 15;252:393-398. Epub 2020 Jul 15.

Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MA, 49503, USA.

Objective: Endometriosis is a common gynecologic disorder often associated with severe pelvic pain and infertility with few known modifiable risk factors. We investigated whether in utero and early life exposures are associated with surgically diagnosed endometriosis among adolescents and young adults.

Study Design: This case-control study, including 295 laparoscopically-confirmed endometriosis cases and 309 population-based controls aged <25 years, was conducted using data from The Women's Health Study: From Adolescence to Adulthood which enrolled participants from 2012 to 2018. Information on in utero and early life factors were collected using a modified WERF EPHect questionnaire at enrollment, including their mother's age at delivery, birthweight, gestation length, exposure to smoking in utero and secondhand smoke during childhood up to age 13, and if the participant was breastfed.

Results: Median age at enrollment was 17 years (range 12-24) in cases and 22 years (range 7-24) in controls, with 83 % and 68 % non-Hispanic whites, respectively. The majority of cases (95 %) were rASRM stage I or II at diagnostic surgery. Exposure to breastfeeding in early life was associated with lower odds of endometriosis diagnosis (OR = 0.39, 95 % CI = 0.21-0.74). Exposure to secondhand smoke during childhood due to maternal smoking was associated with increased odds of endometriosis diagnosis (OR = 2.70, 95 % CI = 1.11-6.60).

Conclusions: Among adolescents and young adults, our data suggest exposures to breastfeeding in early life and secondhand smoke during childhood may be associated with endometriosis risk, providing insight into etiologic pathways to be explored in this young population.
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http://dx.doi.org/10.1016/j.ejogrb.2020.07.014DOI Listing
September 2020

Confounding and effect measure modification in reproductive medicine research.

Hum Reprod 2020 05;35(5):1013-1018

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

The majority of research within reproductive and gynecologic health, or investigating ART, is observational in design. One of the most critical challenges for observational studies is confounding, while one of the most important for discovery and inference is effect modification. In this commentary, we explain what confounding and effect modification are and why they matter. We present examples illustrating how failing to adjust for a confounder leads to invalid conclusions, as well as examples where adjusting for a factor that is not a confounder also leads to invalid or imprecise conclusions. Careful consideration of which factors may act as confounders or modifiers of the association of interest is critical to conducting sound research, particularly with complex observational studies in reproductive medicine.
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http://dx.doi.org/10.1093/humrep/deaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453425PMC
May 2020

The importance of mediation in reproductive health studies.

Hum Reprod 2020 06;35(6):1262-1266

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

A mediator is a factor that occurs after the exposure of interest, precedes the outcome of interest (i.e. between the exposure and the outcome) and is associated with both the exposure and the outcome of interest (i.e. is on the pathway between exposure and outcome). Mediation analyses can be valuable in many reproductive health contexts, as mediation analysis can help researchers to better identify, quantify and understand the underlying pathways of the association they are studying. The purpose of this commentary is to introduce the concept of mediation and provide examples that solidify understanding of mediation for valid discovery and interpretation in the field of reproductive medicine.
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http://dx.doi.org/10.1093/humrep/deaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453394PMC
June 2020

Choice of statistical model in observational studies of ART.

Hum Reprod 2020 07;35(7):1499-1504

Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Analyzing data on ART presents unique and sometimes complicated challenges related to choosing the unit(s) of analysis and the statistical model. In this commentary, we provide examples of how these challenges arise and guidance for overcoming them. We discuss the implications of different ways to count treatment cycles, considering the perspectives of research questions, data management and analysis and patient counseling. We present the advantages and disadvantages of different statistical models, and finally, we discuss the definition and calculation of the cumulative incidence of live birth, which is a key outcome of research on ART.
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http://dx.doi.org/10.1093/humrep/deaa050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368396PMC
July 2020

Research priorities for endometriosis differ among patients, clinicians, and researchers.

Am J Obstet Gynecol 2020 06 3;222(6):630-632. Epub 2020 Mar 3.

Department of Epidemiology and Biostatistics, Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ.

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http://dx.doi.org/10.1016/j.ajog.2020.02.047DOI Listing
June 2020

Adverse Pregnancy Outcomes in Endometriosis - Myths and Realities.

Curr Obstet Gynecol Rep 2020 Mar 30;9(1):27-35. Epub 2020 Jan 30.

Department of Epidemiology, Harvard T.H. Chan School of Public Health.

Purpose Of Review: There is increasing interest in the long-term health and comorbid conditions associated with endometriosis for both women and neonates. The purpose of this review was to synthesize and discuss the current state of the literature investigating endometriosis and risk of adverse pregnancy outcomes.

Recent Findings: Methodologic considerations for studying endometriosis and adverse pregnancy outcomes include complexities regarding the comparison population, endometriosis definition, sample size, residual confounding, and interactions. The current research on endometriosis and adverse pregnancy outcomes should be interpreted cautiously. To date, evidence suggests that endometriosis may be associated with higher risk of ectopic pregnancy, placenta previa, preterm birth, and cesarean section. While an association with miscarriage and stillbirth has been consistently observed, the relative risk was small.

Summary: Pregnant women with endometriosis may be at higher risk for certain adverse pregnancy outcomes and may therefore benefit from additional monitoring. However, additional research is needed to confirm these associations and should focus on ensuring studies have internal and external validity, as well as, investigate the potential for differences in endometriosis phenotypes. Moreover, future research should focus on understanding potential mechanisms of association and better understanding how early interventions, through increased monitoring or screening during pregnancy, may improve outcomes.
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http://dx.doi.org/10.1007/s13669-020-00281-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188856PMC
March 2020

Sexual orientation and benign breast disease in a cohort of U.S. women.

Cancer Causes Control 2020 Feb 1;31(2):173-179. Epub 2020 Jan 1.

Division of Adolescent/Young Adult Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.

Purpose: Several studies indicate that sexual minority (e.g., bisexual, lesbian) women may be at an increased risk for breast cancer. However, we know little about how risk factors, such as benign breast disease (BBD)-which can confer nearly a fourfold breast cancer risk increase-may vary across sexual orientation groups.

Methods: Among Nurses' Health Study II participants followed from 1989 to 2013 (n = 99,656), we investigated whether bisexual and lesbian women were more likely than heterosexual women to have breast cancer risk factors including a BBD diagnosis (self-reported biopsy or aspiration confirmed, n = 11,021). Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results: Compared to heterosexuals, sexual minority participants more commonly reported certain breast cancer risk factors including increased alcohol intake and nulliparity. However, sexual minority participants were more likely than heterosexuals to have certain protective factors including higher body mass index and less oral contraceptive use. When evaluating age- and family history-adjusted rates of BBD diagnoses across sexual orientation groups, bisexual (HR 1.04, 95% CI [0.78, 1.38]) and lesbian (0.99 [0.81, 1.21]) women were just as likely as heterosexuals to have a BBD diagnosis. Results were similar after adjusting for other known breast cancer risk factors.

Conclusions: In this cohort of women across the U.S., sexual minorities were more likely than heterosexuals to have some breast cancer risk factors-including modifiable risk factors such as alcohol intake. Heterosexual, bisexual, and lesbian women were equally as likely to have a BBD diagnosis.
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http://dx.doi.org/10.1007/s10552-019-01258-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981065PMC
February 2020

Endometriosis and Risk of Adverse Pregnancy Outcomes.

Obstet Gynecol 2019 09;134(3):527-536

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona; the Channing Division of Network Medicine, the Department of Obstetrics, Gynecology, and Reproductive Biology, the Division of Preventive Medicine, and the Division of Women's Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Nutrition and the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; the MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland; and the Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, East Lansing, Michigan.

Objective: To investigate the relationship between endometriosis and adverse pregnancy outcomes.

Methods: Women between ages 25 and 42 years in 1989 (n=116,429) reported detailed information on pregnancies and reproductive health at baseline and every 2 years thereafter in the Nurses' Health Study II, a cohort study. In 2009, they completed a detailed, pregnancy-focused questionnaire. A total of 196,722 pregnancies were reported. Adverse pregnancy outcomes included spontaneous abortion, ectopic pregnancy, stillbirth, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), preterm birth, and low birth weight. We estimated the relative risks (RRs) and 95% CIs of adverse pregnancy outcomes comparing pregnancies in women with and without a history of laparoscopically confirmed endometriosis using multivariable log-binomial regression, with generalized estimating equations to account for multiple pregnancies per woman.

Results: Endometriosis was associated with a greater risk of pregnancy loss (spontaneous abortion: RR 1.40, 95% CI 1.31-1.49; ectopic pregnancy: RR 1.46, 95% CI 1.19-1.80). Endometriosis was also associated with a greater risk of GDM (RR 1.35, 95% CI 1.11-1.63) and hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.16-1.45).

Conclusions: We observed an association between laparoscopically confirmed endometriosis and several adverse pregnancy outcomes. Future research should focus on the potential biological pathways underlying these relationships to inform screening or preventive interventions.
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http://dx.doi.org/10.1097/AOG.0000000000003410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922084PMC
September 2019

Hyperglycosylated human chorionic gonadotropin as a predictor of ongoing pregnancy.

Am J Obstet Gynecol 2020 01 8;222(1):68.e1-68.e12. Epub 2019 Aug 8.

Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: Hyperglycosylated human chorionic gonadotropin, the predominant human chorionic gonadotropin variant secreted following implantation, is associated with trophoblast invasion.

Objective: To determine whether the initial serum hyperglycosylated human chorionic gonadotropin differs between ongoing and failed pregnancies, and to compare it to total serum human chorionic gonadotropin as a predictor of ongoing pregnancy.

Materials And Methods: Women undergoing fresh/frozen in vitro fertilization cycles at a university-based infertility clinic with an autologous day 5 single embryo transfer resulting in serum human chorionic gonadotropin >3 mIU/mL (n = 115) were included. Human chorionic gonadotropin was measured 11 days after embryo transfer in a single laboratory (coefficient of variation <6%). Surplus frozen serum (-80C) was shipped to Quest Laboratories for measurement of hyperglycosylated human chorionic gonadotropin (coefficient of variation <9.1%). Linear regression analyses adjusted for oocyte age a priori were used to compare human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin in ongoing pregnancies (>8 weeks of gestation) and failed pregnancies (clinical pregnancy loss, biochemical and ectopic pregnancies).

Results: A total of 85 pregnancies (73.9%) were ongoing. Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated (Pearson correlation coefficient 92.14, P < .0001), and mean values of both were positively correlated with blastocyst expansion score (P value test for trend < .0004). Mean human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin were significantly higher in ongoing vs failed pregnancies. Among ongoing pregnancies vs clinical losses, mean hyperglycosylated human chorionic gonadotropin, but not human chorionic gonadotropin, was significantly higher (19.0 vs 12.2 ng/mL, β -8.1, 95% confidence interval -13.0 to -3.2), and hyperglycosylated human chorionic gonadotropin comprised a higher proportion of total human chorionic gonadotropin (4.6% vs 4.1%; risk ratio, 0.79; 95% confidence interval, 0.66-0.94).

Conclusion: Measured 11 days after single blastocyst transfer, hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated, but only mean hyperglycosylated human chorionic gonadotropin and its ratio to total human chorionic gonadotropin were significantly higher in ongoing pregnancies vs clinical pregnancy losses. Further evaluation of hyperglycosylated human chorionic gonadotropin, including in multiple embryo transfers and multiple pregnancy, and using serial measurements, is required.
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http://dx.doi.org/10.1016/j.ajog.2019.08.004DOI Listing
January 2020

Findings from a mobile application-based cohort are consistent with established knowledge of the menstrual cycle, fertile window, and conception.

Fertil Steril 2019 09 1;112(3):450-457.e3. Epub 2019 Jul 1.

Ovia Health, Boston, Massachusetts; Newton Wellesley Hospital, Newton, Massachusetts.

Objective: To investigate the validity of self-reported fertility data generated by a mobile application-based cohort in comparison with data collected by traditional clinical methodologies.

Design: Data were collected from July 2013 to July 2018 through a mobile application designed to track fertility. Bayesian hierarchical models were used to assess day-specific pregnancy probabilities. Descriptive statistics were used to estimate differences in day of ovulation and lengths of menstrual phases and to assess changes in the cervix and ovulation-related symptoms drawing closer to the day of ovulation.

Setting: Not applicable.

Patient(s): Data consisted of 225,596 menstrual cycles from 98,903 women.

Intervention(s): None.

Main Outcome Measure(s): Day-specific probabilities of pregnancy, variability in lengths of the follicular and luteal phases, trends in prevalence of symptoms and cervix changes across the fertile window.

Result(s): Analyses were consistent with established clinical knowledge. Probability of conception was highest during the 5 days before and day of ovulation, with the highest probability occurring the day before ovulation. The average cycle length was 29.6 days, and average lengths of the follicular and luteal phases were 15.8 and 13.7 days, respectively. Closer to day of ovulation, women were more likely to report changes in the cervix corresponding to fluid consistency, feel, position, and openness and symptoms associated with ovulation, including pelvic pain, tender breasts, increased sex drive, and cramps.

Conclusion(s): Components of the menstrual cycle and fertile window, when re-evaluated with a mobile application-based cohort, were found to be consistent with established clinical knowledge, suggesting an agreement between traditional and modern data collection methodologies.
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http://dx.doi.org/10.1016/j.fertnstert.2019.05.008DOI Listing
September 2019

The combined impact of maternal age and body mass index on cumulative live birth following in vitro fertilization.

Am J Obstet Gynecol 2019 12 1;221(6):617.e1-617.e13. Epub 2019 Jun 1.

Department of Obstetrics and Gynecology, Center for Infertility and Reproductive Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: It is critical to evaluate the combined impact of age and body mass index on the cumulative likelihood of live birth following in vitro fertilization, as achieving a lower body mass index before infertility treatment often is recommended for women with overweight and obesity. It is important to consider whether achieving a particular body mass index, thus resulting in an older age at in vitro fertilization cycle start, is beneficial or harmful to the likelihood of live birth.

Objectives: To evaluate the combined impact of age and body mass index on the cumulative live birth rate following in vitro fertilization to inform when delaying in vitro fertilization treatment to achieve a lower body mass index may be beneficial or detrimental to the likelihood of live birth.

Study Design: This is a retrospective study using linked fresh and cryopreserved/frozen cycles from January 2014 to December 2015 from the Society for Reproductive Technology Clinic Outcome Reporting System, representing >90% of in vitro fertilization cycles performed in the United States. The primary outcome was live birth as measured by cumulative live birth rate. Secondary outcomes included implantation rate, clinical pregnancy rate, and miscarriage rate. Poisson and logistic regression were used to calculate risk and odds ratios with 95% confidence intervals to determine differences in implantation, clinical pregnancy, and miscarriage, as appropriate, among first fresh in vitro fertilization cycles compared across age (years) and body mass index (kg/m) categories. Cox regression was used to calculate hazard ratios with 95% confidence intervals to determine differences in the cumulative live birth rate using fresh plus linked frozen embryo transfer cycles.

Results: There were 51,959 first fresh cycles using autologous eggs and 16,067 subsequent frozen embryo transfer cycles. There were 21,395 live births, for an overall cumulative live birth rate of 41.2% per cycle start. The implantation rate, clinical pregnancy rate, and cumulative live birth rate decreased with increasing body mass index and age, and the miscarriage rate increased with increasing body mass index and age (linear trend P<.001 for all). Body mass index had a greater influence on live birth at younger ages as compared with older ages.

Conclusions: Age-related decline in fertility has a greater impact than body mass index on the cumulative live birth rate at older ages, suggesting that taking time to achieve lower body mass index before in vitro fertilization may be detrimental for older women with overweight or obesity. Delaying conception to lose weight before in vitro fertilization should be informed by the combination of age and body mass index.
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http://dx.doi.org/10.1016/j.ajog.2019.05.043DOI Listing
December 2019
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