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Objective: To describe the prevalence of multimorbidity among individuals with primary ovarian insufficiency (POI) and early menopause compared with those with the average age of menopause., Design: Prospective cohort., Setting: Outpatient communities across ten provinces across Canada, available from the Canadian Longitudinal Study on Aging., Patient(s): This prospective cohort encompassed female postmenopausal individuals from the Canadian Longitudinal Study on Aging. The Canadian Longitudinal Study on Aging collected cross-sectional data from 50,000 community-dwelling Canadians aged 45-85 years between 2010 and 2015., Intervention(s): The primary exposure was POI (defined by onset of menopause at the age of <40 years). Comparators included average age of menopause (age, 46-55 years), early menopause (40-45 years), and late-onset menopause (56-65 years) and those who underwent hysterectomy., Main Outcome Measure(s): The primary outcome was multimorbidity, which was defined as two or more chronic conditions. The secondary outcomes were severe multimorbidity (defined as 3 or more chronic conditions) and frequencies of specific chronic conditions among a comprehensive list of 15 individual conditions. We assessed the association between multimorbidity and age at menopause using logistic regression and odds ratios (ORs), with confidence intervals (CIs) set at 95%. The ORs were adjusted for known predictors of multimorbidity, including age, menopausal hormone therapy, education, ethnicity, self-reported loneliness, living alone, body mass index, smoking habits, nutritional risk, social participation, and physical activity., Result(s): A total of 12,339 postmenopausal participants were included, of whom 374 (3.0%) experienced POI and 1,396 (11.3%) experienced early menopause. The prevalence rates of multimorbidity were 64.8% and 51.1% among those with POI and early menopause, respectively. In contrast, only 43.9% of individuals with average age of menopause (age, 46-55 years) had multimorbidity. The OR for multimorbidity in the POI population was 2.5 (95% CI, 2.0-3.1) compared with that in individuals who had the average age of menopause. This relationship was maintained after adjustment for confounders (adjusted OR [aOR], 2.0; 95% CI, 1.5-2.5). The prevalence of severe multimorbidity was also double in the POI group compared with that in the average age group (39.2% vs. 21.1%). There were significantly increased risks of ischemic heart disease (aOR, 2.8; 95% CI, 1.7-4.7), gastric ulcers (aOR, 1.6; 95% CI, 1.1-2.3), and osteoporosis (aOR, 1.6; 95% CI, 1.2-2.1) in the POI group., Conclusion(s): Individuals with POI and early menopause experience increased multimorbidity compared with those undergoing menopause at an average age. This trend persists even after adjusting for significant multimorbidity risk factors., Competing Interests: Declaration of Interests A.K. has nothing to disclose. N.S. has nothing to disclose. A.M. has nothing to disclose. L.E.G. has nothing to disclose. P.R. has nothing to disclose. A.K.S. has nothing to disclose. The opinions expressed in this manuscript are the authors' own and do not reflect the views of the Canadian Longitudinal Study on Aging., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Depressive symptoms are commonly reported during the perimenopause and in the early postmenopausal years. Although menopausal hormone therapy (MHT) is considered the most effective treatment option for vasomotor symptoms, its effect on mood-related symptoms is less established. This study aims to assess interval change in depressive symptoms after initiation of MHT treatment in women seeking care at a Canadian specialized menopause clinic., Methods: Women and female-presenting people attending the St. Joseph's Healthcare Menopause Clinic in Hamilton, Ontario, were invited to participate in this study. Participants (n = 170) completed a self-report questionnaire, which included their medical history as well as validated tools for bothersome symptoms at their initial visit. A shortened version was administered at the follow-up visit 3 to 12 months later with the same validated tools. We sought to examine interval changes on the Center for Epidemiological Studies Depression Scale based on type of treatment used and MHT dose, while controlling for relevant demographic variables (smoking, education level, age)., Results: There was a high rate of depressive symptoms in those seeking specialized menopause care (62%). MHT use was associated with significantly improved depressive symptoms, both alone and in addition to an antidepressant medication ( P < 0.001). Younger age, lower education attainment, and smoking were all associated with higher depression scores., Conclusion: This study supports the use of MHT to improve depressive symptoms experienced by those seeking specialized menopause care. Further investigation into timing of treatment initiation may facilitate a personalized treatment approach to improve quality of life of women in the peri- and postmenopausal years., Competing Interests: Financial disclosures/conflicts of interest: Dr. Shea has received grants from Pfizer. She has served on advisory boards for Eisai, Pfizer, Bio-syent, and Lupin. She has received honorarium from Pfizer, Eisai, Bio-syent, Lupin, and Organon. Dr. Wolfman has received a grant from Pfizer. She has served on advisory boards for Pfizer, Lupin, Knight Pharmaceuticals, and Duchesnay. She has financial relationships with Bayer, Astellas, and Serona. She is the president of the Canadian Menopause Society and is a board member of the International Menopause Society. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

Objective: Sexual dysfunction is very common among middle-aged females. Several factors are considered to influence sexual functioning, including reproductive aging and associated physiological changes as well as life stressors, mental health, and other socioeconomic influences. The objectives of this study are to evaluate the effect of current depressive symptoms on sexual functioning during menopause and to further analyze whether socioeconomic status, age, and antidepressant usage impact this association., Methods: Perimenopausal and postmenopausal women aged 40 to 65 years seeking treatment from a specialized menopause clinic completed a self-report survey with the main outcome measure being the 19-item Female Sexual Function Index quantifying sexual dysfunction. We used the 10-item Center for Epidemiological Studies Depression Scale to estimate a major depressive episode. Statistical analyses were completed to assess the potential associations of socioeconomic factors, age, and antidepressant usage., Results: Of the 269 participants, 61.3% met criteria for a major depressive episode and 67.0% had low sexual function. As predicted, women currently experiencing depressive symptoms had a greater risk of low sexual function during perimenopause and postmenopause. Antidepressant usage, low household income, being postmenopausal, and age also predicted low sexual function., Conclusions: Among perimenopausal and postmenopausal women, current depressive symptoms were associated with low sexual function. A biopsychosocial approach should be considered when exploring effective treatment strategies for sexual concerns among midlife women., Competing Interests: Financial disclosure/conflicts of interest: W.W. receives ongoing funding from Astellas and Bayer, has received past funding from Lupin, is the President of the Canadian Menopause Society, a board member International Menopause Society, co-head Educational Committee International Menopause Society, and a Medical consultant to the Menopause Foundation of Canada. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

Study Question: What is the association between past infertility and the type and timing of menopause in midlife women?, Summary Answer: Women with a history of infertility were more likely to experience surgical menopause overall and had elevated risk of earlier surgical menopause until age 43 years but experienced no differences in the timing of natural menopause., What Is Known Already: Infertility is experienced by 12-25% of women and is thought to reveal a propensity for poor health outcomes, such as chronic illness, later in life. However, little is known about whether infertility is linked with characteristics of the menopausal transition as women age, despite possible shared underlying pathways involving ovarian function and gynecologic disease., Study Design, Size, Duration: Secondary analysis of a prospective cohort study of 13 243 midlife females recruited in Phase 1 of the Alberta's Tomorrow Project (Alberta, Canada) and followed approximately every 4 years (2000-2022)., Participants/materials, Setting, Methods: Data were collected through standardized self-report questionnaires. History of infertility, defined as ever trying to become pregnant for more than 1 year without conceiving, was measured at baseline. Menopause characteristics were measured at each study follow-up. Menopause type was defined as premenopause, natural menopause, surgical menopause (bilateral oophorectomy), or indeterminate menopause (premenopausal hysterectomy with ovarian conservation). Timing of natural menopause was defined as the age at 1 full year after the final menstrual period, and timing of surgical and indeterminate menopause was defined as the age at the time of surgery. We used flexible parametric survival analysis for the outcome of menopause timing with age as the underlying time scale and multinomial logistic regression for the outcome of menopause type. Multivariable models controlled for race/ethnicity, education, parity, previous pregnancy loss, and smoking. Sensitivity analyses additionally accounted for birth history, menopausal hormone therapy, body mass index, chronic medical conditions, and age at baseline., Main Results and the Role of Chance: Overall, 18.2% of women reported a history of infertility. Past infertility was associated with earlier timing of surgical menopause exclusively before age 43 years (age 35: adjusted hazard ratio 3.13, 95% CI 1.95-5.02; age 40: adjusted hazard ratio 1.83, 95% CI 1.40-2.40; age 45: adjusted hazard ratio 1.13, 95% CI 0.87-1.46) as well as greater odds of experiencing surgical menopause compared to natural menopause (adjusted odds ratio 1.40, 95% CI 1.18-1.66). Infertility was not associated with the timing of natural or indeterminate menopause., Limitations, Reasons for Caution: Information on the underlying cause of infertility and related interventions was not collected, which precluded us from disentangling whether associations differed by infertility cause and treatment. Residual confounding is possible given that some covariates were measured at baseline and may not have temporally preceded infertility., Wider Implications of the Findings: Women with a history of infertility were more likely to experience early surgical menopause and may therefore benefit from preemptive screening and treatment for gynecologic diseases to reduce bilateral oophorectomy, where clinically appropriate, and its associated health risks in midlife. Moreover, the lack of association between infertility and timing of natural menopause adds to the emerging knowledge that diminishing ovarian reserve does not appear to be a primary biological mechanism of infertility nor its downstream implications for women's health., Study Funding/competing Interest(s): Alberta's Tomorrow Project is only possible due to the commitment of its research participants, its staff and its funders: Alberta Health, Alberta Cancer Foundation, Canadian Partnership Against Cancer and Health Canada, and substantial in-kind funding from Alberta Health Services. The views expressed herein represent the views of the author(s) and not of Alberta's Tomorrow Project or any of its funders. This secondary analysis is funded by Project Grant Priority Funding in Women's Health Research from the Canadian Institutes of Health Research (Grant no. 491439). N.V.S. is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research. H.K.B. is supported by the Canada Research Chairs Program. E.A.B. is supported by an Early Career Investigator Award in Maternal, Reproductive, Child and Youth Health from the Canadian Institutes of Health Research. A.K.S. has received honoraria from Pfizer, Lupin, Bio-Syent, and Eisai and has received grant funding from Pfizer. N.V.S., H.K.B., and E.A.B. have no conflicts of interest to report., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cannabis is often used by women to manage symptoms of morning sickness during pregnancy, and postpartum stress and anxiety. While exclusive breastfeeding has been recommended for the first 6 months of an infant's life, the presence of cannabinoids in the milk of cannabis users complicates this recommendation. The objective of this study was to investigate the effect of maternal cannabis use on changes in the levels of macronutrients and bioactive factors in breast milk., Methods: Milk was collected from women who were 6-8 weeks postpartum and were either using cannabis post-delivery, had used cannabis during pregnancy, or were non-users. Levels of cannabinoids, macronutrients, lactose, and SIgA were assessed in the milk of all subjects., Results: THC was detected in the milk of women who reported cannabis use during lactation (n = 13, median: 22 ng/mL). Carboxy-THC, 11-hydroxy-THC, CBD, and CBN were also detected in the milk of women who used cannabis postpartum. Relative to non-users (n = 17), lactose levels were higher and SIgA levels were significantly lower in the milk of subjects who used cannabis during lactation (n = 14)., Conclusions: The presence of cannabinoids, along with altered lactose and SIgA levels in the milk of cannabis users, may have implications for infant health., Impact: Metabolites of cannabis are found in breast milk and can accumulate in higher concentrations with ongoing consumption, which is concerning for potential exposure among infants born to mothers who consume cannabis. This work reports that lactose levels are increased and SIgA levels are decreased in the breast milk of cannabis users, relative to the milk of non-users. Change in levels of lactose and SIgA in the milk of cannabis users may have significant implications on infant health, which must be investigated in the future to better inform mothers., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To examine the association between lifetime lactation and risk and duration of frequent vasomotor symptoms (VMS)., Design: Prospective cohort., Setting: USA, 1995-2008., Sample: 2356 parous midlife women in the Study of Women's Health Across the Nation., Methods: Lifetime lactation was defined as the duration of breastfeeding across all births in months. We used generalised estimating equations to analyse risk of frequent VMS and Cox regression to analyse duration of frequent VMS in years., Main Outcome Measures: Frequent VMS (hot flashes and night sweats) were measured annually for 10 years, defined as occurring ≥6 days in the past 2 weeks., Results: Overall, 57.1% of women reported hot flashes and 43.0% reported night sweats during follow-up. Lifetime lactation was inversely associated with hot flashes plateauing at 12 months of breastfeeding (6 months: adjusted odds ratio [AOR] 0.85, 95% confidence interval (CI) 0.75-0.96; 12 months: AOR 0.78, 95% CI 0.65-0.93) and was inversely associated with night sweats in a downward linear fashion (6 months: AOR 0.93, 95% CI 0.81-1.08; 18 months: AOR 0.82, 95% CI 0.67-1.02; 30 months: AOR 0.73, 95% CI 0.56-0.97). Lifetime lactation was associated with shorter duration of hot flashes and night sweats in a quadratic (bell-shaped) fashion. The association was strongest at 12-18 months of breastfeeding and significant for hot flashes (6 months: adjusted hazard ratio [AHR] 1.35, 95% CI 1.11-1.65; 18 months: AHR 1.54, 95% CI 1.16-2.03; 30 months: AHR 1.18, 95% CI 0.83-1.68)., Conclusions: Longer lifetime lactation is associated with decreased risk and duration of frequent VMS., (© 2022 John Wiley & Sons Ltd.)

Introduction: Cannabis is a widely used substance in pregnancy, yet there is a paucity of literature addressing the neuro-behavioural consequences for prenatally exposed children. Our systematic review synthesizes currently available data for the impact of prenatal cannabis use on offspring intelligence and cognitive functioning., Methods: MEDLINE, EMBASE, PsychINFO, CINAHL, and Clinicaltrials.gov were searched. Observational studies comparing prenatal cannabis use to controls were included. Offspring neuro-behavioural outcomes were grouped in prespecified domains of (1) intelligence and (2) cognitive functioning. Random-effect models were performed for meta-analyses when at least three studies reported the same outcome. All others were summarized qualitatively. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework was used to assess evidence certainty., Results: Of the 1982 reviewed studies (n = 523,107 patients), 28 were included. Significant heterogeneity and cohort redundancy limited meta-analysis. Very low-quality evidence from pooled analyses showed no significant associations between prenatal cannabis exposure and attention [standardized mean difference = -0.27 (95% CI = -0.60 to 0.07)], global intelligence quotient [-0.16 (-0.42 to 0.10)], reading [-0.05 (-0.29 to 0.20)], written comprehension [-0.09 (-0.40 to 0.22)], spelling [-0.04 (-0.26 to 0.17)], and mathematics [-0.01 (-0.15 to 0.13)]. No significant associations were found between prenatal cannabis exposure for all other outcomes. Individual studies reported significant differences between the heavy use groups and non-exposed, although this did not prove to be significant when outcomes were pooled., Conclusions: The current review did not find a clear association between prenatal cannabis use and offspring neuro-behavioural outcomes. However, evidence was low quality and heterogenous. Further prospective investigation is needed to elucidate any potential association between prenatal cannabis use and long-term neuro-developmental outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Perimenopausal and postmenopausal women commonly report sleep disruption and insomnia. Behavioral interventions may be safe alternatives for patients who are unwilling to begin pharmacological treatments because of adverse effects, contraindications, or personal preference., Objective: The primary objective is to assess the efficacy of behavioral interventions on sleep outcomes among perimenopausal and postmenopausal women, as measured using standardized scales and objective methods (polysomnography, actigraphy). The secondary objective is to evaluate the safety of these methods through occurrence of adverse events., Evidence Review: Searches were performed within MEDLINE (OVID interface, 1946 onward), Embase (OVID interface, 1974 onward), Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Web of Science (Core collection) using a search strategy developed in consultation with a health sciences librarian. Title/abstract and full-text screenings were performed in duplicate, and relevant studies were selected based on inclusion and exclusion criteria set to identify randomized controlled trials evaluating the effects of behavioral interventions on sleep quality. Risk of bias assessments were done using the Cochrane Risk of Bias 2 tool, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to assess the certainty of the body of evidence. Data were pooled in a meta-analysis using a random-effects model., Findings: Nineteen articles reporting results from 16 randomized controlled trials were included, representing a total of 2,108 perimenopausal and postmenopausal women. Overall, behavioral interventions showed a statistically significant effect on sleep outcomes (standardized mean difference [SMD], -0.62; 95% confidence interval [CI], -0.88 to -0.35; I2 = 93.4%). Subgroup analyses revealed that cognitive behavioral therapy (SMD, -0.40; 95% CI, -0.70 to -0.11; I2 = 72.7%), physical exercise (SMD, -0.57; 95% CI, -0.94 to -0.21; I2 = 94.0%), and mindfulness/relaxation (SMD, -1.28; 95% CI, -2.20 to -0.37; I2 = 96.0%) improved sleep, as measured using both subjective (eg, Pittsburg Sleep Quality Index) and objective measures. Low-intensity (SMD, -0.91; 95% CI, -1.59 to -0.24; I2 = 96.8) and moderate-intensity exercise (SMD, -0.21; 95% CI, -0.34 to -0.08; I2 = 0.0%) also improved sleep outcomes. No serious adverse events were reported. Overall risk of bias ranged from some concern to serious, and the certainty of the body of evidence was assessed to be of very low quality., Conclusions and Relevance: This meta-analysis provides evidence that behavioral interventions, specifically, cognitive behavioral therapy, physical exercise, and mindfulness/relaxation, are effective treatments for improving sleep outcomes among perimenopausal and postmenopausal women., Competing Interests: Financial disclosure/conflicts of interest: Alison K. Shea has received honoraria from Pfizer and Bio-Syent and has received grant funding from Pfizer. The other authors have nothing to disclose., (Copyright © 2022 by The North American Menopause Society.)

Objective: The aim of this study was to examine the association between duration of lifetime lactation and age at natural menopause., Methods: In this prospective cohort study, we analyzed parous premenopausal women in the multiethnic Study of Women's Health Across the Nation who were followed approximately annually for 10 years (1995-2008). Lifetime lactation was defined as the duration of breastfeeding across all births in months. Age at natural menopause was defined as age in years after 12 consecutive months of amenorrhea after the final menstrual period for no other reported cause. We used Cox proportional hazard models to analyze time to natural menopause with age as the underlying time scale. Multivariable models controlled for education, race/ethnicity, parity, smoking, body mass index, and oral contraceptive use., Results: Among 2,377 women, 52.6% experienced natural menopause during follow-up and reported a valid final menstrual period date. The small, crude association between lifetime lactation up to 24 months and later age at natural menopause attenuated to nonsignificance in adjusted models (6 months: adjusted hazard ratio [AHR], 0.96; 95% confidence interval (CI), 0.87-1.06; 12 months: AHR, 0.95; 95% CI, 0.82-1.11; 18 months: AHR, 0.96; 95% CI, 0.82-1.13; 24 months: AHR, 0.99; 95% CI, 0.84-1.16)., Conclusions: Duration of lifetime lactation was not associated with age at natural menopause after controlling for sociodemographic characteristics., Competing Interests: Financial disclosure/conflicts of interest: A.K.S. has received honoraria from Pfizer and Bio-Syent and has received grant funding from Pfizer. P.D.F. is a shareholder and consultant and receives payment in convertible notes from ViTAA medical devices. N.V.S. and E.A.B. have no disclosures to report., (Copyright © 2022 by The North American Menopause Society.)

Objectives: This study aimed to identify recommendations given to breastfeeding individuals by Canadian cannabis dispensary employees, since the legalization of recreational cannabis in 2018., Methods: This was a nationwide cross-sectional study conducted from November 2020 to January 2021. A mystery caller approach was used to identify recommendations given to breastfeeding individuals seeking a product for "relaxation." This study was modelled on similar studies which assessed recommendations given to pregnant women looking for cannabis products to manage nausea and vomiting (Vastis V, Shea AK, Vincent S, Metz TD. 275: Are canadian cannabis dispensaries counselling pregnant women appropriately? Am. J. Obstet. Gynecol. 2020;222: S187.(Abst). Lusero I, Paltrow LM, Rosenbloom N. Recommendations from cannabis dispensaries about first-trimester cannabis use Obstet Gynecol 2018;132:781-2.). The primary outcome was the recommendation of a cannabis product. Secondary outcomes included stated benefits of cannabis, recommended discussion with health care provider, length of call, rationale for recommendation, and reported source of information on which the recommendation was based., Results: The majority (79.4%) of employees of the 714 Canadian dispensaries contacted recommended against a cannabis product for "relaxation" while breastfeeding. The recommendations from dispensary employees were often (80%) provided without a specific reason, whereas a minority referenced published research (2%) and opinion (17.6%). Cannabis products were rarely (3.3%) classified as safe in breastfeeding. Approximately 76.6% of dispensary employees recommended contacting a health care provider, while 2.4% recommended against., Conclusions: Although a high proportion of dispensary employees recommended against using a cannabis product during lactation, there were still 20.6% that did recommend use, which contrasts the current public health guidelines and is not supported by the paediatric and obstetric societies. These findings highlight the need for further education about the safety of cannabis products while breastfeeding., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A growing body of literature has suggested that the perimenopause and the early postmenopausal years are associated with an increased risk of experiencing symptoms of depression and the development of first-onset and recurrent episodes of major depressive disorder. Multiple risk factors have been identified, including stressful life events and lower socioeconomic status, as well as early life adversity. The objective of the current study was to characterize the influence of early life childhood maltreatment and incident depression among women experiencing bothersome menopausal symptoms. Participants were recruited from two university-affiliated specialty clinics caring for women with bothersome menopausal symptoms. Assessments included the Childhood Trauma Questionnaire (CTQ), the Center for Epidemiological Studies - Depression (CES-D) scale and the Greene Climacteric Scale. Findings from this cross-sectional study indicate that adverse childhood experiences, as measured using the CTQ, were highly prevalent among women seeking care for bothersome menopausal symptoms (66%). Further, a greater score on the CTQ was significantly associated with higher CES-D scores, as well as with a greater burden of menopausal symptoms, after adjusting for confounding. Our findings lend support to the growing body of literature suggesting that early life stress affects mental health well into adulthood.

Osteoarthritis (OA) is a highly prevalent condition characterized by degradation of the joints. OA and cardiovascular disease (CVD) are leading contributors to disease burden worldwide, with a high level of overlap between the risk factors and occurrence of both conditions. Chief among the risk factors that contribute to OA and CVD are sex and age, which are both independent and interacting traits. Specifically, the prevalence of both conditions is higher in older women, which may be mediated by the occurrence of menopause. Menopause represents a significant transition in a women's life, and the rapid decline in circulating sex hormones, estrogen and progesterone, leads to complex physiological changes. Declines in hormone levels may partially explain the increase in prevalence of OA and CVD in post-menopausal women. In theory, the use of hormone therapy (HT) may buffer adverse effects of menopause; however, it is unclear whether HT offers protective effects for the onset or progression of these diseases. Studies have shown mixed results when describing the influence of HT on disease risk among post-menopausal women, which warrants further exploration. The roles that increasing age, female sex, HT, and CVD play in OA risk demonstrate that OA is a multifaceted condition. This review provides a timely consolidation of current literature and suggests aims for future research directions to bridge gaps in the understanding of how OA, CVD, and HT interact in post-menopausal women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mei, Williams, Webb, Shea, MacDonald and Al-Khazraji.)

Objective: Provide strategies for improving the care of perimenopausal and postmenopausal women based on the most recent published evidence., Target Population: Perimenopausal and postmenopausal women., Benefits, Harms, and Costs: Target population will benefit from the most recent published scientific evidence provided via the information from their health care provider. No harms or costs are involved with this information since women will have the opportunity to choose among the different therapeutic options for the management of the symptoms and morbidities associated with menopause, including the option to choose no treatment., Evidence: Databases consulted were PubMed, MEDLINE, and the Cochrane Library for the years 2002-2020, and MeSH search terms were specific for each topic developed through the 7 chapters., Validation Methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: physicians, including gynaecologists, obstetricians, family physicians, internists, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; pharmacists; medical trainees, including medical students, residents, fellows; and other providers of health care for the target population., Summary Statements: RECOMMENDATIONS., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Recreational cannabis use was legalized in Canada in October 2018. We aimed to determine the prevalence and correlates of cannabis consumption among pregnant individuals in a single Canadian city following national legalization., Methods: Over the period May to October 2019, we distributed an anonymous cross-sectional survey to pregnant patients attending family practice, midwifery, and low-risk and high-risk obstetrics clinics in Hamilton, Ontario. Eligibility was based on English literacy and current pregnancy. The survey included questions regarding lifetime and in-pregnancy cannabis use, intent for postpartum use and patterns of use. We also collected demographic information. We calculated descriptive statistics and performed logistic regression analyses to explore the relations between cannabis consumption and demographic characteristics., Results: Of 531 pregnant individuals approached, 478 agreed and were able to participate, for a 90% participation rate. Among these 478 respondents, 54 (11%) reported consuming cannabis at some point during the pregnancy and 20 (4%) reported currently consuming cannabis. Among the 460 respondents who intended to breastfeed, 23 (5%) planned to consume cannabis during the postpartum period. Of 20 current users, 13 (65%) reported consuming cannabis at least weekly and 19 (95%) reported nausea, sleep problems or anxiety as reasons for use. Respondents without postsecondary education had 10.0-fold (95% confidence interval [CI] 4.6-23.5) greater odds of prenatal cannabis consumption than university-educated respondents. In addition, respondents who reported that their partners used cannabis had 3.9-fold (95% CI 2.2-7.3) greater odds of prenatal cannabis consumption than those who reported that their partners did not use cannabis., Interpretation: Lower educational attainment and partners' cannabis consumption were associated with greater odds of inpregnancy cannabis use. These results may help to inform early intervention strategies to decrease cannabis consumption during this vulnerable period of fetal and neonatal development., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

Objective: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used medications for mood and anxiety disorders in women. Many women need to continue or initiate these medications during pregnancy, but there is concern about potential withdrawal effects in the newborn, referred to as neonatal abstinence syndrome (NAS). The reason why some infants remain asymptomatic while others are affected has not been elucidated. The objective of this study was to examine whether genetic differences in maternal drug metabolism influence the incidence of NAS., Methods: Women who took Selective serotonin reuptake inhibitors s/SNRIs during pregnancy were recruited from obstetrical clinics. DNA was extracted from saliva samples for genetic analyses of cytochrome P450 (CYP) enzyme polymorphisms. Delivery and NAS data were collected from electronic medical records., Results: Ninety-five women participated. The overall NAS rate was 16.2%. Mild NAS was seen in 13.8% of neonates and severe NAS, in 2%. One-quarter (25%) of the neonates with mild withdrawal symptoms were born to mothers with polymorphisms associated with slower metabolism of their particular antidepressant, but this association was not statistically significant., Conclusion: Importantly, the overall rate of NAS in our study was lower than previously reported. Maternal CYP polymorphisms did not affect the rate of NAS in neonates exposed to SSRIs/SNRIs in utero. This study lends added assurance to patients requiring SSRIs or SNRIs during pregnancy., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Our objective was to examine the recommendations that Canadian dispensary employees are giving to women regarding cannabis use for nausea and vomiting of pregnancy (NVP) since the legalization of recreational cannabis in 2018. We conducted a nationwide cross-sectional study of licensed cannabis dispensaries in 2019, wherein a mystery caller stated they were 8 weeks pregnant and experiencing nausea and vomiting and asked for recommendations about cannabis. Our research was modeled after the primary study done in Colorado by Dickson and colleagues in 2018. An overwhelming majority of dispensaries (93%) in our study recommended against the use of a cannabis product for NVP, which contrasted significantly to the findings of the Colorado study, in which 70% of dispensaries recommended a cannabis product. These findings suggest that Canadian dispensary employees have been adequately educated about the dangers of cannabis use during pregnancy and are helpful from a public health lens., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. All rights reserved.)

The World Health Organization estimates that more than 260 million people are affected by depression worldwide, a condition that imposes a significant burden to individuals, their families, and society. Women seem to be disproportionately more affected by depression than men, and it is now clear that some women may experience windows of vulnerability for depression at certain reproductive stages across their life span, including the midlife transition. For some, age, the presence of cardiovascular or metabolic problems, and the emergence of significant, bothersome vasomotor symptoms and sleep problems may result in a compounded, deleterious impact on well-being and overall functioning., Competing Interests: Disclosure Dr C.N. Soares has received research and educational grants from the Ontario Brain Institute (OBI), the Ontario Research Funds–Research Excellence (ORF-RE), and the AHSC AFP Innovation Fund. He has served as a consultant for Sunovion, Merck, Otsuka and Lundbeck. Dr A.K. Shea has received honorarium from Pfizer. BioSyent and Sprout Pharmaceuticals. She has also received a research grant from Pfizer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The objective of this study is to describe the association of premature ovarian insufficiency (POI) and early menopause on bone mineral density (BMD) and osteoporosis in a large cohort of women living in Canada., Methods: Cross-sectional baseline data from a deeply characterized cohort (female participants) of the Canadian Longitudinal Study on Aging was used. Additional bio-psycho-social characteristics that may influence bone health and the development of osteoporosis were explored., Results: The mean age of women at the time of baseline assessment was 65 years (N = 12,339). When comparing women with POI to those with early and normal age of menopause, there was no difference in hip BMD between groups, but women in the POI group were more likely to have a higher rate of self-reported osteoporosis (21.9% vs 16.7%) and have used osteoporosis drugs (11.39% vs 7.63%). After adjustment, POI was found to increase the odds of osteoporosis, as diagnosed using BMD. Current cigarette smoking was found to influence this association. Protective factors included obesity and current hormone therapy use, but not the duration of hormone therapy use. Women in the POI group were more likely to be obese, have decreased physical activity, and were more likely to be current smokers., Conclusion: These results confirm findings from smaller cohorts illustrating that POI is associated with osteoporosis. Increasing understanding of the sequelae associated with an earlier loss of ovarian function will aid in targeting earlier screening and intervention strategies for women in Canada and abroad., Competing Interests: Financial disclosure/conflicts of interest: A.K.S. has received honorarium from Pfizer, BioSyent. She has also received a grant from Pfizer. P.R. holds a Tier 1 Canada Research Chair in Geroscience and the Raymond and Margaret Labarge Chair in Research and Knowledge Application for Optimal Aging. The other authors have nothing to disclose., (Copyright © 2021 by The North American Menopause Society.)

Objective: Rates of cannabis use during pregnancy and while breastfeeding are increasing in Canada. Some observational studies have found associations between cannabis use in pregnancy and low birthweight, preterm labour, and admission to the intensive care unit. This study aimed to evaluate women's perceptions about transmission of cannabis to the fetus, and whether receiving information from a health care provider influenced their decision to stop using cannabis during pregnancy., Methods: Pregnant women presenting to obstetrical, midwifery, and family practice clinics in the greater Hamilton, Ontario area were asked to complete an anonymous survey. Chi-square tests were used to investigate whether patient knowledge was influenced by health care providers or by self-directed learning and if this information influenced their decision to discontinue cannabis use., Results: Of the 478 women surveyed, the vast majority perceived that cannabis is transmitted to the fetus during pregnancy and to the infant while breastfeeding (94.3% and 91.2%, respectively). The majority of women (99%) indicated that the advent of cannabis legalization did not influence their choice to use cannabis in pregnancy. Women who continued to use cannabis during pregnancy were more likely to report receiving information on cannabis from a health care provider (52%) than those who chose to discontinue use in pregnancy (35%) (P = 0.035)., Conclusions: In our study, the proportion of pregnant women who understood that cannabis could be transmitted to the fetus in utero and to the infant via breastmilk was high. Despite this, 4.2% of women reported that they continued to use cannabis in pregnancy. More work is needed to understand why some women continue to use cannabis in pregnancy despite being informed of its risks., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the association between menopausal status, hormone therapy (HT) use and the presence of depressive symptoms among middle-aged women in Canada., Methods: Cross-sectional baseline data from 13,216 women aged 45 to 64 years from the Canadian Longitudinal Study on Aging (CLSA) was used. The association between menopausal status (pre- vs postmenopausal) and self-reported symptoms of depression based on a score of 10 or more on the Center for Epidemiologic Studies Short Depression Scale-10 was assessed using logistic regression. Use and duration of use of HT, time since menopause, age at onset of menopause, and socioeconomic status and other contextual variables were explored for the association with depression., Results: Overall, 18.4% of middle-aged women in the CLSA data were identified as depressed using the Center for Epidemiologic Studies Short Depression Scale-10. Based on the logistic regression models, women reporting premature menopause (before the age of 40 years) and postmenopausal women currently using HT had 1.45 (1.07-1.97) and 1.21 (1.02-1.44) greater odds of having depression. Chi-square analyses showed that women with depressive symptoms were more likely to have low education, low household incomes, live alone, be nulliparous, and have low social support., Conclusions: Our findings highlight the association between depression and premature menopause among midlife women. Current HT use may be a proxy for more severe menopausal vasomotor symptoms, a known risk factor for depressive symptoms. Identification of risk factors, including social determinants of health, age at menopause, and menopausal symptoms can help guide clinicians when assessing mental health. : Video Summary:http://links.lww.com/MENO/A576.

The objective of this study is to determine whether maternal antidepressant use during pregnancy influences uteroplacental hemodynamics, thereby affecting fetal growth and gestational age at delivery. The secondary aim was to determine the incidence of neonatal abstinence syndrome (NAS) among infants exposed to antidepressant medications. The charts of women who received obstetrical care and had a history of depression from January 2014 to December 2016 at Mount Sinai Hospital in Toronto, Canada, were reviewed. Exclusion criteria were substance abuse; narcotic or lithium use at the time of delivery.In total, 205 women met the inclusion criteria (92 took antidepressants; 113 women did not). There were no significant differences in umbilical artery pulsatility index (PI), gestational age at delivery, or birth weight when comparing women based on antidepressant use. A small proportion (18%) of neonates had mild withdrawal symptoms; one baby had a score (≥ 8) consistent with severe NAS. In women with a history of depression, there was no difference in uteroplacental hemodynamics as measured by third trimester Doppler ultrasonography when comparing women who took antidepressant medication versus those who did not. The large majority of babies who were exposed to antidepressants in utero did not show withdrawal symptoms. These results lend support for the relative safety of antidepressants during pregnancy.

Purpose: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are used as alternative treatments for the vasomotor symptoms of menopause in women who are unwilling or unable to receive hormone therapy. These agents have been associated with sexual dysfunction and xerostomia (dry mouth), but the effect on the vagina has not been studied. The objective of this study was to determine the effect of SSRIs and SNRIs on the vaginal epithelium and sexual function in postmenopausal women, using both subjective and objective measures. Materials and methods: A cross-sectional study of postmenopausal women not using any local or systemic estrogen therapy was conducted. The main outcomes included the Female Sexual Function Index (FSFI), vaginal epithelial maturation index (MI), and pH. Results: Sixty-six women were recruited, 30 using SSRIs/SNRIs and 36 who were not (control). Both the proportion of superficial vaginal epithelial cells and the total MI were higher in the SSRI/SNRI group ( p  = 0.006 and p  = 0.047, respectively). There were no significant differences in FSFI scores, vaginal pH, or total MI values. Conclusion: The use of serotonin reuptake inhibiting drugs does not appear to have a negative influence on the vaginal epithelium and associated vaginal atrophy.

Importance: Hormone therapy (HT) has been suggested for protection against age-related muscle weakness in women. However, the potential for HT-associated health risks necessitates a better understanding of the direction and magnitude of the association between HT and health outcomes, such as lean body mass (LBM)., Objective: To determine whether HT was associated with reduced LBM loss compared with not receiving HT among postmenopausal women aged 50 years and older., Data Sources: MEDLINE, Embase, AgeLine, CINAHL, and SportDiscus (searched from inception until April 25, 2018)., Study Selection: For this systematic review and meta-analysis, randomized clinical trials including postmenopausal women undergoing HT and control groups of women not receiving HT were selected by 2 reviewers. Studies were included if LBM or fat-free mass were measured as an outcome. Studies with participants from hospitals, long-term care facilities, or with specific diseases were excluded., Data Extraction and Synthesis: Information regarding study characteristics and outcome measures were extracted by 1 reviewer and verified by another. Risk of bias was evaluated. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used to abstract data and assess data quality/validity. Data were pooled using a fixed-effects model., Main Outcomes and Measures: The primary study outcome was the overall absolute change in LBM (measured in kilograms), captured by dual-energy x-ray absorptiometry, dual-photon absorptiometry, or bioelectrical impedance analysis imaging., Results: Of 8961 studies that met selection criteria, 12 were included, with a total of 4474 recruited participants. Of the participants, mean (SD) age was 59.0 (6.1) years. Data on ethnicity were collected by 2 of the studies. Of the 22 HT intervention arms, 15 used estrogen-progesterone combination HT and 7 used estrogen-only HT. Control participants were women who received no HT at all or who received placebo. The median follow-up duration was 2 years (range, 6 months to 6 years). Seven treatment arms showed a loss of LBM, and 14 were protective. Overall, HT users lost 0.06 kg (95% CI, -0.05 to 0.18) less LBM compared with control participants, but the difference was not statistically significant (P = .26). The results were unchanged when stratified based on treatment type and dosage, duration of follow-up, time since menopause, study quality, and type of LBM measurement, with HT users losing between 0.06 kg more to 0.20 kg less LBM compared with control participants for all strata. The quality of evidence based on GRADE was low., Conclusions and Relevance: This systematic review and meta-analysis did not show a significant beneficial or detrimental association of HT with muscle mass. Although muscle retention in aging women is of crucial importance, these findings suggest that interventions other than HT should be explored.

Objective: Premature ovarian failure associated with Turner syndrome presents clinicians with a vast range of health concerns, including infertility, cardiovascular disease, and decreased bone mineral density, in addition to psychological sequelae. Hormone therapy is paramount in managing these complications, but the additional needs in the postpartum period for those who are able to carry out a successful pregnancy have not been described., Methods: We present a case of severe postpartum depression (PPD) with psychotic features in a patient with Turner syndrome, which presented at 4 weeks after the birth of her first child via egg donation RESULTS:: We describe the case of a previously well 32-year-old patient with an 46 X, i(Xq) karyotype, who went through a 4-week intensive inpatient treatment course for PPD, requiring electroconvulsant therapy for persistent infanticidal and suicidal ideation. It was hypothesized that an estrogen-depleted state secondary to premature ovarian insufficiency and lactation may have been more pronounced during her postpartum course when hormone levels dramatically decrease. To buffer the dramatic drop in sex steroid levels postpartum for her second pregnancy, she was immediately started on estrogen and progesterone replacement, and did not experience any change in mood or similar psychiatric disturbance during this postpartum course. Four years after the PPD episode, her mood remains stable., Conclusion: This case highlights the complex interplay between ovarian steroids, depletion of their levels, and psychiatric sequelae. The postpartum period represents a particularly vulnerable time for patients with premature ovarian insufficiency, which requires very close monitoring and early replacement of depleted hormone levels.

Objective: Our aim was to characterize the management and outcome of women admitted to a tertiary high-risk obstetrics unit with a short cervix (≤25 mm), measured on transvaginal ultrasound (TVS), and to determine the latency period from diagnosis to delivery., Methods: A retrospective chart review of women admitted to the High Risk Obstetrics Unit at Sunnybrook Health Sciences Centre between 2005-2011 with an ultrasound-identified short cervix was done., Results: A total of 110 women admitted for a short cervix between 2005-2011 (N = 56 singletons; N = 54 twin gestations) met the inclusion criteria. The mean latency to delivery was 62.6 days; mean GA at delivery was 33.9 weeks. Following 7 and 14 days of admission, 5.5% and 11.8% of women had delivered, respectively. Preterm birth occurred in 70% of all women. Cervical length was a significant factor in predicting latency among singletons, whereas the length of stay in hospital for activity restriction was not., Conclusions: Although many women with a short cervix delivered preterm, only a small proportion delivered within 2 weeks of admission. Although it is not clear whether inpatient management improves the pregnancy outcome, these findings have implications for both patient care and health resources., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Prenatal serotonin reuptake inhibitor exposure is common and neonatal outcomes vary greatly, often leading to confusion about whether to use or even continue antenatal use of these antidepressants. Importantly, some but not all infants are affected, which raises questions about how maternal drug metabolism contributes to fetal drug exposure. To address this key question, our paper reviews the role of key maternal, fetal, and placental pharmacokinetic, metabolic, and genetic factors that affect the extent of fetal drug exposure. Considering the role of these factors may further our understanding of variables that may assist in optimizing maternal psychopharmacotherapy during pregnancy and neonatal outcomes.

Pregnancy is associated with major physiological changes and adaptation to these changes is crucial for normal fetal development. Heightened emotional stress during pregnancy may interfere with the necessary adaptation and lead to dysregulation of the two major stress response systems: the Hypothalamic-Pituitary-Adrenal (HPA) Axis and the Autonomic Nervous System (ANS). Negative effects on the fetus of such maladaptation have been documented in both animals and humans and range from poor birth outcomes to negative impacts on neurodevelopment, as well as long term emotional and behavioural disturbances. Conversely, it has been hypothesized that low levels of maternal prenatal stress may actually have an adaptive value for the offspring. Investigation of these associations employing physiological markers and repeated measures throughout pregnancy and postpartum of both the mother and the offspring, is required in order to understand the various effects of prenatal stress on the development of the offspring. It is also crucial to explore the possibility of variable periods of vulnerability throughout gestation. The aim of this commentary is to reexamine the current literature on the ill-effects of maternal stress during pregnancy on the offspring and to explore avenues for future treatment and prevention.

Depression during pregnancy has been associated with a number of adverse outcomes, but the underlying physiological mechanisms involved remain unclear. The purpose of this study was to examine the effects of maternal depression during pregnancy on the autonomic modulation of heart rate, in a naturalistic setting. Eighty-one pregnant women were studied between 25 and 31 weeks of gestation and were identified as either Depressed (n = 46), or healthy, Control (n = 35), based on depression scores and lifetime psychiatric history. Subjects wore a 24-h Holter recorder to measure time-domain and frequency-domain of heart rate variability (HRV). Pregnant women in the Depressed Group had significantly reduced time-domain measures: standard deviation of all 24-h NN intervals (SDNN) and the standard deviation of the averages of NN intervals in all 5-min segments of the entire recording (SDANN) (P = 0.013, 0.016, respectively), as well as higher heart rates while asleep (P = 0.028), compared to Controls, after controlling for age, smoking, and antidepressant (AD) medication. The low frequency/high frequency (LF/HF) ratio during the sleeping hours was associated with higher depression scores (R = 0.24; P = 0.041). HRV measures improved in women taking AD medication. The autonomic nervous system may be affected in women experiencing depression during pregnancy, indicating a possible decreased parasympathetic (vagal) influence. Women taking AD medication showed some improvement in HRV measures. These data suggest that psychophysiological changes occur in women experiencing depression during pregnancy.

Maternal smoking during pregnancy is associated with several adverse developmental outcomes in the offspring. These include preterm delivery, spontaneous abortion, growth restriction, increased risk of sudden infant death syndrome (SIDS), as well as long-term behavioral and psychiatric disorders. However, the underlying physiological mechanisms for these ill-effects are not fully understood. The aim of this paper is to review the animal and human data to date, linking in utero smoke exposure to negative neurodevelopmental outcomes. It is known that nicotine from cigarette smoke exerts its effects by affecting placental vasculature, and also by nicotinic acetylcholine receptor binding in fetal membranes. Thus, subsequent consequences involve a cascade of events causing not only dysregulation of the nicotinic and muscarinic, but also catecholaminergic and serotonergic neurotransmitter systems. These observations provide some insight into how smoking can impair neurodevelopment, but the long-term neurotransmitter involvement in dysregulation of emotion and attention awaits further elucidation. It is important that pregnant women are warned of the detrimental effects of smoking, and encouraged to abstain for healthy fetal development.

The purpose of this study was to examine the effects of maternal depression and anxiety on the cortisol awakening response (CAR), a marker of the hypothalamic-pituitary-adrenal (HPA) axis function, during pregnancy. Sixty-six pregnant women were studied between 25 and 33 weeks of gestation and were identified as either Depressed (n=33) or healthy, Control (n=33), based on depression scores and lifetime psychiatric history. Saliva samples were collected (passive drool) upon awakening and at +30 and +60 min thereafter. The CAR was not significantly different between women who were depressed during pregnancy compared to healthy control women. However, women taking antidepressant (AD) medication showed an attenuated CAR (time x AD use interaction, p=0.06). Childhood maltreatment (as measured with the Childhood Trauma Questionnaire) was associated with a lower baseline cortisol concentration explaining 12% of the variance, controlling for wake-up time and AD use. There is a complex interplay of factors involved in the HPA axis regulation of vulnerable women during pregnancy, including depression, anxiety, early life stress and psychotropic medication use, which remain unclear. The CAR may provide important information about the maternal HPA axis during pregnancy and warrants further investigation in larger cohorts.

Objective: To analyse the statements given by tobacco industry defence witnesses during trial testimonies and depositions in second-hand smoke cases and in parallel, to review criticisms of epidemiology in industry-funded publications in order to identify strategies for discrediting epidemiologic evidence on passive smoking health effects., Methods: A collection of depositions and trial testimony transcripts from tobacco industry-related lawsuits filed in the United States during the 1990s, was compiled and indexed by the Tobacco Deposition and Trial Testimony Archive (DATTA). Statements in DATTA made by expert witnesses representing the tobacco industry relating to the health effects of passive smoking were identified and reviewed. Industry-supported publications within the peer-reviewed literature were also examined for statements on exposure misclassification, meta-analysis, and confounding., Results: The witnesses challenged causation of adverse health effects of passive smoking by citing limitations of epidemiologic research, raising methodological and statistical issues, and disputing biological plausibility. Though not often cited directly by the witnesses, the defence tactics mirrored the strategies used in industry-funded reports in the peer-reviewed literature., Conclusion: The tobacco industry attempted to redirect the focus and dialogue related to the epidemiologic evidence on passive smoking. This approach, used by industry experts in trial testimony and depositions, placed bias as a certain alternative to causation of diseases related to passive smoking and proposed an unachievable standard for establishing the mechanism of disease.

Cytotoxic T lymphocytes (CTL) target multiple epitopes in human immunodeficiency virus (HIV)-infected persons, and are thought to influence the viral set point. The extent to which HLA class I allele expression predicts the epitopes targeted has not been determined, nor have the relative contributions of responses restricted by different class I alleles within a given individual. In this study, we performed a detailed analysis of the CTL response to optimally defined CTL epitopes restricted by HLA class I A and B alleles in individuals who coexpressed HLA A2, A3, and B7. The eight HIV-1-infected subjects studied included two subjects with acute HIV infection, five subjects with chronic HIV infection, and one long-term nonprogressor. Responses were heterogeneous with respect to breadth and magnitude of CTL responses in individuals of the same HLA type. Of the 27 tested epitopes that are presented by A2, A3, and B7, 25 were targeted by at least one person. However, there was wide variation in the number of epitopes targeted, ranging from 2 to 17. The A2-restricted CTL response, which has been most extensively studied in infected persons, was found to be narrowly directed in most individuals, and in no cases was it the dominant contributor to the total HIV-1-specific CTL response. These results indicate that HLA type alone does not predict CTL responses and that numerous potential epitopes may not be targeted by CTL in a given individual. These data also provide a rationale for boosting both the breadth and the magnitude of HIV-1-specific CTL responses by immunotherapy in persons with chronic HIV-1 infection.

We longitudinally measured T-cell receptor transcript frequencies of human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) in an individual with rapidly progressive disease and high levels of viremia. CTL clones elicited during acute HIV-1 infection were present at the time of death, despite absent functional CTL responses, arguing against clonal deletion as a mechanism for the decline of CTL responses observed during HIV-1 infection.

Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38(+) activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.

Cellular immune responses are thought to be an important antiviral host defense, but the relationship between virus-specific T-helper and cytotoxic-T-lymphocyte (CTL) responses has not been defined. To investigate a potential link between these responses, we examined functional human immunodeficiency virus type 1 (HIV-1)-specific memory CTL precursor frequencies and p24-specific proliferative responses in a cohort of infected untreated persons with a wide range of viral loads and CD4 cell counts. Levels of p24-specific proliferative responses positively correlated with levels of Gag-specific CTL precursors and negatively correlated with levels of plasma HIV-1 RNA. These data linking the levels of HIV-specific CTL with virus-specific helper cell function during chronic viral infection provide cellular immunologic parameters to guide therapeutic and prophylactic vaccine development.