Prepregnancy plant-based diets and risk of hypertensive disorders of pregnancy.

BACKGROUND: Plant-based diets have been associated with a lower risk of cardiovascular disease in nonpregnant adults, but specific evidence for their effects on risk of hypertensive disorders of pregnancy is scarce. OBJECTIVE: This study aimed to evaluate the prospective association between adherence to plant-based diets before pregnancy and the risk for hypertensive disorders of pregnancy. We hypothesized that women with higher adherence to plant-based diets would have a lower risk for hypertensive disorders of pregnancy. STUDY DESIGN: We followed 11,459 parous women (16,780 singleton pregnancies) without chronic diseases, a history of preeclampsia, and cancers who participated in the Nurses' Health Study II (1991-2009), which was a prospective cohort study. Diet was assessed every 4 years using a validated food frequency questionnaire from which we calculated the plant-based diet index (higher score indicates higher adherence) to evaluate the health associations of plant-based diets among participants while accounting for the quality of plant-based foods. Participants self-reported hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension. We estimated the relative risk of hypertensive disorders of pregnancy in relation to plant-based diet index adherence in quintiles using generalized estimating equations log-binomial regression while adjusting for potential confounders and accounting for repeated pregnancies for the same woman. RESULTS: The mean (standard deviation) age at first in-study pregnancy was 35 (4) years. A total of 1033 cases of hypertensive disorders of pregnancy, including 482 cases of preeclampsia (2.9%) and 551 cases of gestational hypertension (3.3%) were reported. Women in the highest quintile of plant-based diet index were significantly associated with a lower risk for hypertensive disorders of pregnancy than women in the lowest quintile (relative risk, 0.76; 95% confidence interval, 0.62-0.93). There was an inverse dose-response relationship between plant-based diet index and risk for hypertensive disorders of pregnancy. The multivariable-adjusted relative risk (95% confidence interval) of hypertensive disorders of pregnancy for women in increasing quintiles of plant-based diet index were 1 (ref), 0.93 (0.78-1.12), 0.86 (0.72-1.03), 0.84 (0.69-1.03), and 0.76 (0.62-0.93) with a significant linear trend across quintiles (P trend=.005). This association was slightly stronger for gestational hypertension (relative risk, 0.77; 95% confidence interval, 0.60-0.99) than for preeclampsia (relative risk, 0.80; 95% confidence interval, 0.61-1.04). Mediation analysis suggested that body mass index evaluation for dietary assessment and pregnancy explained 39% (95% confidence interval, 15%-70%]) of the relation between plant-based diet index and hypertensive disorders of pregnancy and 48% (95% confidence interval, 12%-86%]) of the relation between plant-based diet index and gestational hypertension. CONCLUSION: Higher adherence to plant-based diets was associated with a lower risk of developing hypertensive disorders of pregnancy. Much of the benefit seems to be related to improved weight control.

Association of Gestational Diabetes With Subsequent Long-Term Risk of Mortality.

Importance: Gestational diabetes has been associated with numerous chronic diseases. However, few studies have examined the association of gestational diabetes with long-term mortality risk. Objective: To investigate the associations between gestational diabetes and long-term risks of total and cause-specific mortality. Design, Setting, and Participants: This cohort study analyzed participants of the Nurses' Health Study II who were followed for 30 years (1989-2019). Participants included US female nurses aged 25 to 42 years who reported at least 1 pregnancy (≥6 months) at 18 years or older across their reproductive life span. Data were analyzed from May 1, 2022, to May 25, 2023. Exposure: Gestational diabetes across the reproductive life span. Main Outcomes and Measures: Hazard ratios (HRs with 95% CIs) for total and cause-specific mortality were estimated by Cox proportional hazards regression models. Results: A total of 91 426 parous participants were included, with a mean (SD) age of 34.9 (4.7) years and a body mass index of 24.1 (4.7) at baseline. During a follow-up period of 2 609 753 person-years, 3937 deaths were documented, including 255 deaths from cardiovascular disease and 1397 from cancer. Participants with a history of gestational diabetes had a higher crude mortality rate than those without a history of gestational diabetes (1.74 vs 1.49 per 1000 person-years; absolute difference = 0.25 per 1000 person-years). The corresponding HR for total mortality was 1.28 (95% CI, 1.13-1.44), which did not materially change after additional adjustment for potential confounders and lifestyle factors during the reproductive life span (HR, 1.25; 95% CI, 1.11-1.41). The association persisted regardless of the subsequent development of type 2 diabetes and was more robust among participants who adopted less healthy lifestyles; experienced gestational diabetes in 2 or more pregnancies (HR, 1.48; 95% CI, 0.99-2.19); had gestational diabetes both in the initial and subsequent pregnancies (HR, 1.71; 95% CI, 1.11-2.63); and concurrently reported hypertensive disorders in pregnancy (HR, 1.80; 95% CI, 1.21-2.67), preterm birth (HR, 2.46; 95% CI, 1.66-3.64), or low birth weight (HR, 2.11; 95% CI, 1.21-3.68). Cause-specific mortality analyses revealed that gestational diabetes was directly associated with the risk of mortality due to cardiovascular disease (HR, 1.59; 95% CI, 1.03-2.47). Additionally, gestational diabetes was inversely associated with cancer mortality (HR, 0.76; 95% CI, 0.59-0.98); however, it was only evident among participants who later developed type 2 diabetes. Conclusions and Relevance: Results of this cohort study suggest that participants who reported a history of gestational diabetes exhibited a small but elevated risk of subsequent mortality over 30 years. The findings emphasize the importance of considering gestational diabetes as a critical factor in later-life mortality risk.

Association of early life physical and sexual abuse with premature mortality among female nurses: prospective cohort study.

OBJECTIVE: To explore associations between early life physical and sexual abuse and subsequent risk of premature mortality (death before age 70 years). DESIGN: Prospective cohort study. SETTING: The Nurses' Health Study II (2001-19). PARTICIPANTS: 67 726 female nurses aged 37-54 years when completing a violence victimization questionnaire in 2001. MAIN OUTCOME MEASURES: Hazard ratios and 95% confidence intervals for total and cause specific premature mortality by childhood or adolescent physical and sexual abuse, estimated by multivariable Cox proportional hazard models. RESULTS: 2410 premature deaths were identified over 18 years of follow-up. Nurses who experienced severe physical abuse or forced sexual activity in childhood and adolescence had a higher crude premature mortality rate than nurses without such abuse in childhood or adolescence (3.15 v 1.83 and 4.00 v 1.90 per 1000 person years, respectively). The corresponding age adjusted hazard ratios for premature deaths were 1.65 (95% confidence interval 1.45 to 1.87) and 2.04 (1.71 to 2.44), respectively, which were materially unchanged after further adjusting for personal characteristics and early life socioeconomic status (1.53, 1.35 to 1.74, and 1.80, 1.50 to 2.15, respectively). Cause specific analyses indicated that severe physical abuse was associated with a greater risk of mortality due to external causes of injury and poisoning (multivariable adjusted hazard ratio 2.81, 95% confidence interval 1.62 to 4.89), suicide (3.05, 1.41 to 6.60), and diseases of the digestive system (2.40, 1.01 to 5.68). Forced sexual activity as a child and adolescent was associated with greater risk of mortality due to cardiovascular disease (2.48, 1.37 to 4.46), external injury or poisoning (3.25, 1.53 to 6.91), suicide (4.30, 1.74 to 10.61), respiratory disease (3.74, 1.40 to 9.99), and diseases of the digestive system (4.83, 1.77 to 13.21). The association of sexual abuse with premature mortality was stronger among women who smoked or had higher levels of anxiety during adulthood. Smoking, low physical activity, anxiety, and depression each explained 3.9-22.4% of the association between early life abuse and premature mortality. CONCLUSION: Early life physical and sexual abuse could be associated with a greater risk of adult premature mortality.

Association of laparoscopically-confirmed endometriosis with long COVID-19: a prospective cohort study.

BACKGROUND: Women are at greater risk than men of developing chronic inflammatory conditions and "long COVID." However, few gynecologic health risk factors for long COVID-19 have been identified. Endometriosis is a common gynecologic disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiological mechanisms proposed for long COVID-19. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID-19. OBJECTIVE: This study aimed to investigate the association between history of endometriosis before SARS-CoV-2 infection and risk of long COVID-19. STUDY DESIGN: We followed 46,579 women from 2 ongoing prospective cohort studies-the Nurses' Health Study II and the Nurses' Health Study 3-who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires before the pandemic (1993-2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, polymerase chain reaction, or antibody test) and long-term COVID-19 symptoms (≥4 weeks) defined by the Centers for Disease Control and Prevention were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases). RESULTS: Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation, and 1598 (43.8%) reported experiencing long COVID-19 symptoms. Most women were non-Hispanic White (95.4%), with a median age of 59 years (interquartile range, 44-65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID-19 (adjusted risk ratio, 1.22; 95% confidence interval, 1.05-1.42) compared with those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID-19 as having symptoms for ≥8 weeks (risk ratio, 1.28; 95% confidence interval, 1.09-1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID-19 by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend indicating that the association may be stronger in women aged <50 years (<50 years: risk ratio, 1.37; 95% confidence interval, 1.00-1.88; ≥50 years: risk ratio, 1.19; 95% confidence interval, 1.01-1.41). Among persons who developed long COVID-19, women with endometriosis reported on average 1 additional long-term symptom compared with women without endometriosis. CONCLUSION: Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID-19. Healthcare providers should be aware of endometriosis history when treating patients for signs of persisting symptoms after SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.

History of infertility and risk of breast cancer: a prospective cohort study.

PURPOSE: Research on infertility and risk of breast cancer has been conflicting, potentially because many well-established breast cancer risk factors, such as pregnancy history, are strongly correlated with infertility. METHODS: We followed participants in the Nurses' Health Study II from 1989 to 2015 (n = 103,080) for the development of invasive breast cancer and calculated Hazard Ratios (HR) and 95% confidence intervals (CI) using Cox regression. Participants with a self-reported history of infertility (12 months of trying without conception) were compared to gravid women with no history of infertility. We classified breast cancer by menopausal status and investigated mediation by reproductive factors. RESULTS: Over 26 years of follow-up, 26,208 (25.4%) women reported a history of infertility, and 3,201 women were newly diagnosed with invasive breast cancer. We observed no association between infertility history and risk of overall breast cancer (HR: 1.05, 95% CI: 0.97-1.14) or premenopausal breast cancer (RR: 0.93, 95% CI: 0.83-1.03). However, we observed a modest association between history of infertility and risk of postmenopausal breast cancer (HR: 1.13, 95% CI: 1.00-1.28), approximately 50% of which could be attributed to lower total parity and later age at first birth (95% CI: 8.2%-91.0%). CONCLUSIONS: Women with a history of infertility were at increased risk of postmenopausal breast cancer. Older age at first birth and lower total parity explained approximately half of the association between infertility and risk of postmenopausal breast cancer.

A prospective cohort study of infertility and cancer incidence.

OBJECTIVE: To investigate the association between infertility and the incidence of invasive cancer. DESIGN: Prospective cohort study (1989-2015). SETTING: Not applicable. PATIENT(S): A total of 103,080 women aged 25-42 years in the Nurses' Health Study II who were cancer-free at baseline (1989). INTERVENTION(S): The infertility status (failure to conceive after 1 year of regular, unprotected sex) and causes of infertility were self-reported at baseline and biennial follow-up questionnaires. MAIN OUTCOME MEASURE(S): Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian, and postmenopausal breast) or non-obesity-related (all other cancers). We fit the Cox proportional-hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between infertility and cancer incidence. RESULT(S): During 2,149,385 person-years of follow-up, 26,208 women reported a history of infertility, and we documented 6,925 incident invasive cancer cases. After adjusting for body mass index and other risk factors, women who reported infertility had a higher risk of developing cancer than gravid women without a history of infertility (HR, 1.07; 95% CI, 1.02-1.13). This association was stronger among obesity-related cancers (HR, 1.13; 95% CI, 1.05-1.22; vs. non-obesity-related cancers, HR, 0.98; 95% CI, 0.91-1.06) and, in particular, obesity-related reproductive cancers (postmenopausal breast, endometrial, and ovarian cancers; HR, 1.17; 95% CI, 1.06-1.29) and was stronger among women who first reported infertility earlier in life (≤25 years, HR, 1.19; 95% CI, 1.07-1.33; 26-30 years, HR, 1.11; 95% CI, 0.99-1.25; >30 years, HR, 1.07; 95% CI, 0.94-1.22; P trend < .001). CONCLUSION(S): A history of infertility may be associated with the risk of developing obesity-related reproductive cancers; further study is needed to elucidate the underlying mechanisms.

Prepregnancy Migraine, Migraine Phenotype, and Risk of Adverse Pregnancy Outcomes.

BACKGROUND AND OBJECTIVE: Migraine is a highly prevalent neurovascular disorder among reproductive-aged women. Whether migraine history and migraine phenotype might serve as clinically useful markers of obstetric risk is not clear. The primary objective of this study was to examine associations of prepregnancy migraine and migraine phenotype with risks of adverse pregnancy outcomes. METHODS: We estimated associations of self-reported physician-diagnosed migraine and migraine phenotype with adverse pregnancy outcomes in the prospective Nurses' Health Study II (1989-2009). Log-binomial and log-Poisson models with generalized estimating equations were used to estimate relative risks (RRs) and 95% CIs for gestational diabetes mellitus (GDM), preeclampsia, gestational hypertension, preterm delivery, and low birthweight. RESULTS: The analysis included 30,555 incident pregnancies after cohort enrollment among 19,694 participants without a history of cardiovascular disease, diabetes, or cancer. After adjusting for age, adiposity, and other health and behavioral factors, prepregnancy migraine (11%) was associated with higher risks of preterm delivery (RR = 1.17; 95% CI = 1.05-1.30), gestational hypertension (RR = 1.28; 95% CI = 1.11-1.48), and preeclampsia (RR = 1.40; 95% CI = 1.19-1.65) compared with no migraine. Migraine was not associated with low birthweight (RR = 0.99; 95% CI = 0.85-1.16) or GDM (RR = 1.05; 95% CI = 0.91-1.22). Risk of preeclampsia was somewhat higher among participants with migraine with aura (RR vs no migraine = 1.51; 95% CI = 1.22-1.88) than migraine without aura (RR vs no migraine = 1.30; 95% CI = 1.04-1.61; p-heterogeneity = 0.32), whereas other outcomes were similar by migraine phenotype. Participants with migraine who reported regular prepregnancy aspirin use had lower risks of preterm delivery (<2×/week RR = 1.24; 95% CI = 1.11-1.38; ≥2×/week RR = 0.55; 95% CI = 0.35-0.86; p-interaction < 0.01) and preeclampsia (<2×/week RR = 1.48; 95% CI = 1.25-1.75; ≥2×/week RR = 1.10; 95% CI = 0.62-1.96; p-interaction = 0.39); however, power for these stratified analyses was limited. DISCUSSION: Migraine history, and to a lesser extent migraine phenotype, appear to be important considerations in obstetric risk assessment and management. Future research should determine whether aspirin prophylaxis may be beneficial for preventing adverse pregnancy outcomes among pregnant individuals with a history of migraine.

Breastfeeding duration and subsequent risk of mortality among US women: A prospective cohort study.

Background: Breastfeeding has been associated with a reduced maternal long-term risk of chronic diseases, but its association with mortality is poorly known. Methods: We included 166,708 female United States (US) nurses from the Nurses' Health Study (1986-2016) and the Nurses' Health Study II (1989-2019) who experienced at least one pregnancy lasting at least six months across their reproductive lifespan. Hazard ratios and 95% confidence intervals (CI) for mortality according to lifetime breastfeeding duration were estimated with time-dependent Cox proportional hazards regression models. Findings: During 4,705,160 person-years of follow-up, 36,634 deaths were documented in both cohorts, including 9880 from cancer and 7709 from cardiovascular disease (CVD). Lifetime total breastfeeding duration was associated with a lower subsequent risk of all-cause mortality in a non-linear manner (p-value for non-linearity=0.0007). The pooled multivariable-adjusted hazard ratios of all-cause mortality were 0.95 (95% CI: 0.92 to 0.98), 0.94 (95% CI: 0.91 to 0.98), 0.93 (95% CI: 0.90 to 0.97), and 0.93 (95% CI: 0.89 to 0.97), respectively, for women reporting lifetime total breastfeeding duration of 4-6, 7-11, 12-23, and ≥24 months, compared to women who breastfed for ≤3 months over their reproductive lifespan. Cause-specific analysis showed a similar pattern of non-linear inverse associations between lifetime total breastfeeding duration and CVD and cancer mortality (both p-values for non-linearity <0.01). There was no evidence of interactions between breastfeeding duration and pre-pregnancy lifestyle factors on mortality risk. Interpretation: Parous women with longer lifetime breastfeeding duration had a modestly lower risk of mortality. Funding: The National Institutes of Health grants.

Risk of cardiovascular disease in women and men with subfertility: the Trøndelag Health Study.

OBJECTIVE: To investigate the association between subfertility and risk of cardiovascular disease (CVD) outcomes. DESIGN: Prospective study. SETTING: Population-based cohort. PATIENT(S): We studied 31,629 women and 17,630 men participating in the Trøndelag Health Study. INTERVENTION(S): Self-reported subfertility. As men were not directly asked about fertility, male partners of female participants were identified through linkage to the Medical Birth Registry of Norway and assigned the fertility information obtained from their partners. MAIN OUTCOME MEASURE(S): The primary outcomes were stroke and coronary heart disease in women and men with and without a history of subfertility. The secondary outcomes were myocardial infarction and angina (subgroups of coronary heart disease) and any CVD (stroke or coronary heart disease). Information on CVD was available by linkage to hospital records. We used Cox proportional hazards models adjusted for age at participation in the Trøndelag Health Study (linear + squared), birth year, smoking history, cohabitation, and education. Cardiometabolic factors were assessed in separate models. RESULT(S): A total of 17% of women and 15% of men reported subfertility. In women, subfertility was modestly associated with an increased risk of stroke (age-adjusted hazard ratio [aaHR], 1.19; 95% confidence interval [CI], 1.02-1.39; adjusted hazard ratio [aHR]; 1.18; 95% CI, 1.01-1.37) and coronary heart disease (aaHR, 1.19; 95% CI, 1.06-1.33; aHR, 1.16; 95% CI, 1.03-1.30) compared with fertile women. In men, we observed a weak positive association for stroke (aaHR, 1.11; 95% CI, 0.91-1.34; aHR, 1.10; 95% CI, 0.91-1.33) and a weak inverse association for coronary heart disease (aaHR, 0.92; 95% CI, 0.81-1.05; aHR, 0.93; 95% CI, 0.81-1.06). CONCLUSION(S): We observed modestly increased risks of CVD outcomes in women and some weak associations in men, although with no strong statistical evidence on sex differences. We acknowledge that we were only able to include men linked to pregnancies ending at 12 completed gestational weeks or later, potentially resulting in selection bias and misclassification of history of subfertility in analyses of male partners. Despite the large sample size, our results indicate the need for larger studies to obtain precise results in both sexes and determine whether there are true sex differences.

A prospective study of the association between SARS-CoV-2 infection and COVID-19 vaccination with changes in usual menstrual cycle characteristics.

BACKGROUND: Despite anecdotal reports, the impacts of SARS-CoV-2 infection or COVID-19 vaccination on menstrual health have not been systemically investigated. OBJECTIVE: This study aimed to examine the associations of SARS-CoV-2 infection and COVID-19 vaccination with menstrual cycle characteristics. STUDY DESIGN: This study prospectively observed 3858 premenopausal women in the Nurses' Health Study 3 living in the United States or Canada who received biannual follow-up questionnaires between January 2011 and December 2021 and completed additional monthly and quarterly surveys related to the COVID-19 pandemic between April 2020 and November 2021. History of positive SARS-CoV-2 test, COVID-19 vaccination status, and vaccine type were self-reported in surveys conducted in 2020 and 2021. Current menstrual cycle length and regularity "before COVID-19" were reported at baseline between 2011 and 2016, and current menstrual cycle length and regularity "after COVID-19" were reported in late 2021. Pre- to post-COVID change in menstrual cycle length and regularity was calculated between reports. Logistic or multinomial logistic regression models were used to assess the associations between SARS-CoV-2 infection and COVID-19 vaccination and change in menstrual cycle characteristics. RESULTS: The median age at baseline and the median age at end of follow-up were 33 years (range, 21-51) and 42 years (range, 27-56), respectively, with a median follow-up time of 9.2 years. This study documented 421 SARS-CoV-2 infections (10.9%) and 3527 vaccinations (91.4%) during follow-up. Vaccinated women had a higher risk of increased cycle length than unvaccinated women (odds ratio, 1.48; 95% confidence interval, 1.00-2.19), after adjusting for sociodemographic and behavioral factors. These associations were similar after in addition accounting for pandemic-related stress. COVID-19 vaccination was only associated with change to longer cycles in the first 6 months after vaccination (0-6 months: odds ratio, 1.67 [95% confidence interval, 1.05-2.64]; 7-9 months: odds ratio, 1.43 [95% confidence interval, 0.96-2.14]; >9 months: odds ratio, 1.41 [95% confidence interval, 0.91-2.18]) and among women whose cycles were short, long, or irregular before vaccination (odds ratio, 2.82 [95% confidence interval, 1.51-5.27]; odds ratio, 1.10 [95% confidence interval, 0.68-1.77] for women with normal length, regular cycles before vaccination). Messenger RNA and adenovirus-vectored vaccines were both associated with this change. SARS-CoV-2 infection was not associated with changes in usual menstrual cycle characteristics. CONCLUSION: COVID-19 vaccination may be associated with short-term changes in usual menstrual cycle length, particularly among women whose cycles were short, long, or irregular before vaccination. The results underscored the importance of monitoring menstrual health in vaccine clinical trials. Future work should examine the potential biological mechanisms.

Associations of birth weight and later life lifestyle factors with risk of cardiovascular disease in the USA: A prospective cohort study.

Background: Low birth weight has been associated with a greater risk of cardiovascular disease (CVD). However, the interaction between low birth weight and adult lifestyle factors on the risk of CVD remains unclear. Methods: We included 20,169 men from the Health Professionals Follow-up Study (HPFS, 1986-2016), 52,380 women from the Nurses' Health Study (NHS, 1980-2018), and 85,350 women from the Nurses' Health Study II (NHS II, 1991-2017) in the USA who reported birth weight and updated data on adult body weight, smoking status, physical activity, and diet every 2-4 years. Incident cases of CVD, defined as a combined endpoint of fatal and nonfatal coronary heart disease (CHD) and stroke, were self-reported and confirmed by physicians through reviewing medical records. Findings: During 4,370,051 person-years of follow-up, 16,244 incident CVD cases were documented, including 12,126 CHD and 4118 stroke cases. Cox proportional hazards regression models revealed an increased risk of CHD during adulthood across categories of decreasing birth weight in all cohorts (all P for linear trend <0.001). Additionally, we found an additive interaction between decreasing birth weight and unhealthy lifestyles on the risk of CHD among women, with a pooled relative excess risk due to interaction of 0.06 (95% CI: 0.04-0.08). The attributable proportions of the joint effect were 23.0% (95% CI: 11.0-36.0%) for decreasing birth weight alone, 67.0% (95% CI: 58.0-75.0%) for unhealthy lifestyle alone, and 11.0% (95% CI: 5.0-17.0%) for their additive interaction. Lower birth weight was associated with a greater stroke risk only among women, which was independent of later-life lifestyle factors. Interpretation: Lower birth weight may interact synergistically with unhealthy lifestyle factors in adulthood to further increase the risk of CHD among women. Funding: The National Institutes of Health grants.

Cardiovascular Risk Factors Mediate the Long-Term Maternal Risk Associated With Hypertensive Disorders of Pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia, are associated with an increased risk of CVD. OBJECTIVES: The purpose of this study was to evaluate associations between HDP and long-term CVD and identify the proportion of the association mediated by established CVD risk factors. METHODS: Parous participants without CVD in the Nurses' Health Study II (n = 60,379) were followed for incident CVD from first birth through 2017. Cox proportional hazards models estimated HRs and 95% CIs for the relationship between HDP and CVD, adjusting for potential confounders, including prepregnancy body mass index, smoking, and parental history of CVD. To evaluate the proportion of the association jointly accounted for by chronic hypertension, hypercholesterolemia, type 2 diabetes, and changes in body mass index, we used the difference method. RESULTS: Women with HDP in first pregnancy had a 63% higher rate of CVD (95% CI: 1.37-1.94) compared with women with normotensive pregnancies. This association was mediated by established CVD risk factors (proportion mediated = 64%). The increased rate of CVD was higher for preeclampsia (HR: 1.72; 95% CI: 1.42-2.10) than gestational hypertension (HR: 1.41; 95% CI: 1.03-1.93). Established CVD risk factors accounted for 57% of the increased rate of CVD for preeclampsia but 84% for gestational hypertension (both P < 0.0001). CONCLUSIONS: Established CVD risk factors arising after pregnancy explained most (84%) of the increased risk of CVD conferred by gestational hypertension and 57% of the risk among women with preeclampsia. Screening for chronic hypertension, hypercholesterolemia, type 2 diabetes, and overweight/obesity after pregnancy may be especially helpful in CVD prevention among women with a history of HDP.

Association of infertility with premature mortality among US women: Prospective cohort study.

Background: Infertility has been associated with common chronic non-communicable diseases. However, the association of infertility with long-term mortality is unclear. Methods: We followed 101,777 women aged 25-42 years at enrollment between 1989 and 2017. Biennial questionnaires updated participants' infertility status and underlying reasons for infertility throughout their reproductive lifespan. Hazard ratios (HRs) for the associations of infertility with the risk of premature mortality (death before age 70 years) were estimated using Cox proportional hazards models. Findings: During 28 years of follow-up, 2174 women died before age 70 years. Infertility was associated with an HR of 1.26 (95% confidence interval: 1.15 to 1.38) for premature death. This relation was largely driven by deaths from cancer (HR = 1.22, 1.08 to 1.39) and was stronger among women reporting infertility at a younger age (HR = 1.35, 1.19 to 1.52 for age ≤ 25 years; 1.23, 1.10 to 1.38 for age 26-30 years; and 1.10, 0.91 to 1.32 for age > 30 years, compared to no infertility). The premature mortality risk was also higher for women who didn't become pregnant after their first report of infertility (HR = 1.39, 1.25 to 1.54) than among women who reported at least one pregnancy after infertility (HR = 1.12, 1.00 to 1.26). When contributing diagnoses of infertility were evaluated, a greater risk of all-cause mortality was associated with infertility due to ovulatory disorders (HR = 1.28, 1.09 to 1.51) and endometriosis (HR = 1.50, 1.22 to 1.83). Interpretation: Infertility may be associated with a greater risk of premature mortality, particularly cancer mortality.

Enrollment of female participants in United States drug and device phase 1-3 clinical trials between 2016 and 2019.

BACKGROUND: Historically, females have been underrepresented in clinical trials evaluating the safety and efficacy of investigational drugs and devices. We assessed participation by sex in recent clinical trials. METHODS: We extracted data over a 4-year period (2016-2019) from ClinicalTrials.gov on US-based, pharmaceutical industry or government-funded Phase 1-3 clinical trials of drugs and devices. We included trials with adult cardiovascular, psychiatric, and cancer endpoints whose protocol planned to enroll both sexes. Average proportions of females enrolled per trial were described overall and by disease area. RESULTS: Across 1433 trials including 302,664 participants in our analysis, on average, 41.2% were female. Females were underrepresented compared with their proportion of the disease population in cardiovascular disease trials (41.9% female participants vs. 49% female population with cardiovascular disease). In psychiatry, where females comprise 60% of patients, the mean participation of females in clinical trials was 42.0%. Similarly, for cancer trials, where 51% of patients are female, only 41.0% of cancer clinical trial participants were female. For each therapeutic area analyzed, the participation of females in clinical trials fell short of the benchmark derived from national prevalence data. CONCLUSIONS: While the participation of females in clinical trials has improved compared to previous reports, sex-based gaps still persist between trial populations and those expected to use these drugs/devices based on distributions of diseases in the population. Given potential sex-based differences in treatment responses and toxicities, adequate inclusion of females in clinical trials remains critical.

Physical activity before pregnancy and the risk of hypertensive disorders of pregnancy.

BACKGROUND: It is unclear whether prepregnancy physical activity influences the risk of hypertensive disorders of pregnancy and whether any impact is similar for preeclampsia and gestational hypertension. OBJECTIVE: To evaluate the relation of prepregnancy physical activity with hypertensive disorders of pregnancy and its alignment with the current recommendations for physical activity for the general population. STUDY DESIGN: We studied 28,147 singleton pregnancies from 18,283 women without chronic hypertension, cardiovascular disease, or cancer, participating in the Nurses' Health Study-II between 1989 and 2010. The women self-reported their physical activity before pregnancy and pregnancy complications, including preeclampsia and gestational hypertension. Logistic regression models using generalized estimating equations to account for within-woman correlations across pregnancies were used to estimate the relative risk (95% confidence interval) of preeclampsia and gestational hypertension across quartiles of prepregnancy physical activity, adjusting for age at pregnancy, parity, smoking, multivitamin use, infertility history, marital status, race, year of pregnancy, and history of preeclampsia. RESULTS: We identified 842 (3.0%) pregnancies with preeclampsia and 905 (3.2%) pregnancies with gestational hypertension. Physical activity before pregnancy was related to a lower risk of hypertensive disorders of pregnancy (relative risk, 0.75 [95% confidence interval, 0.65-0.87] for women in the highest quartile compared with the lowest quartile). This relation was driven by a 39% lower risk of gestational hypertension (relative risk, 0.61; 95% confidence interval, 0.50-0.76) comparing women in the highest quartile of physical activity (≥30.6 metabolic equivalents of task-hours/week) vs women in the lowest quartile (<6.0 metabolic equivalents of task-hours/week). Women whose moderate physical activity levels exceeded those recommended in the Physical Activity Guidelines for Americans (>5 hours/week) had a 50% lower (relative risk, 0.50; 95% confidence interval, 0.36-0.69) risk of gestational hypertension than women who did not meet this recommendation (<2.5 hours/week). For vigorous physical activity, the risk of gestational hypertension was lower among the women who met (1.25-2.5 hours/week; relative risk, 0.77; 95% confidence interval, 0.64-0.93) or exceeded (>2.5 hours/week; relative risk, 0.76; 95% confidence interval, 0.62-0.92) the recommendations than women whose activity levels were below those recommended. Physical activity was not related to the risk of preeclampsia (relative risk, 0.93; 95% confidence interval, 0.76-1.14). CONCLUSION: Physical activity before pregnancy may lower the risk of developing gestational hypertension but not preeclampsia.

Birth weight and long-term risk of mortality among US men and women: Results from three prospective cohort studies.

Background: Weight at birth has been associated with the development of various adult diseases, but its association with mortality remains unclear. Methods: We included 22,389 men from the Health Professionals Follow-up Study (1994-2018) and 162,231 women from the Nurses' Health Study (1992-2018) and the Nurses' Health Study II (1991-2019). The hazard ratios (HRs) of mortality according to birth weight were estimated by Cox proportional hazards regression models with adjustment for potential confounders. Findings: Compared to women reporting a birth weight of 3.16-3.82 kg, the pooled HRs for all-cause mortality were 1.13 (95% CI, 1.08 to 1.17), 0.99 (95% CI, 0.96 to 1.02), 1.04 (95% CI, 1.00 to 1.08), and 1.03 (95% CI, 0.96 to 1.10), respectively, for women with a birth weight of <2.5, 2.5-3.15, 3.83-4.5, and >4.5 kg. In cause-specific mortality analyses, women reporting birth weight >4.5 kg had a higher risk of cancer mortality (HR=1.15, 95% CI: 1.00 to 1.31), whereas women with a birth weight <2.5 kg had an elevated risk of mortality from cardiovascular diseases (HR=1.15; 95% CI, 1.05 to 1.25) and respiratory diseases (HR=1.35; 95% CI, 1.18 to 1.54). Birth weight was unrelated to all-cause mortality among men, but cause-specific mortality analyses showed an inverse association with cardiovascular disease mortality and a positive association with cancer mortality (p for linear trend = 0.012 and 0.0039, respectively). Interpretation: low birth weight was associated with a greater risk of cardiovascular and respiratory disease mortality among women, while large birth weight was associated with a greater cancer mortality risk in both men and women. Funding: The National Institutes of Health grants U01-HL145386, U01-CA176726, R01-HL034594, R01-HL088521, UM-CA186107, P01-CA87969, R01-CA49449, R01-CA67262, U01-HL145386, U01-CA167552, R01-HL35464, and R24-ES028521-01 support this study.

Lifestyle Changes and Long-term Weight Gain in Women With and Without a History of Gestational Diabetes Mellitus: A Prospective Study of 54,062 Women in the Nurses' Health Study II.

OBJECTIVE: We examined lifestyle factors with midlife weight change according to history of gestational diabetes mellitus (GDM) in a large longitudinal female cohort. RESEARCH DESIGN AND METHODS: In the Nurses' Health Study II, we categorized changes in lifestyle within 4-year periods and estimated their associations with concurrent changes in body weight (kilograms) among parous women after age 40 years by GDM history status (N = 54,062; 5.3% with a history of GDM) for the following: diet quality (Alternate Healthy Eating Index [AHEI]), leisure-time physical activity (PA), alcohol consumption, and smoking status. RESULTS: Over a median follow-up of 13 years, average 4-year weight gain was 1.10 and 1.33 kg for women with and without prior GDM, respectively. Women with improved diet quality had favorable 4-year weight change, particularly those with a history of GDM (AHEI change [95% CI] from low to high -2.97 kg [-4.34, -1.60] vs. -1.19 kg [-1.41, -0.96] for GDM vs. non-GDM, respectively; P heterogeneity = 0.04). Increasing PA was associated with weight maintenance for GDM women only (PA increase [95% CI] from low to high 0.26 kg [-0.25, 0.77] vs. 0.90 kg [0.80, 1.01] for GDM vs. non-GDM, respectively; P heterogeneity = 0.02). For both GDM and non-GDM women, weight change did not differ significantly with change in alcohol consumption, while women who quit smoking had significant weight gain (4.38 kg for GDM and 3.85 kg for non-GDM). CONCLUSIONS: Improvements in diet quality and PA were related to less weight gain in midlife among parous women, and the benefit of such improvements on weight management was particularly pronounced among women with a history of GDM.

The role of cardiovascular risk factors in maternal cardiovascular disease according to offspring birth characteristics in the HUNT study.

A history of preterm or small (SGA) or large (LGA) for gestational age offspring is associated with smoking and unfavorable levels of BMI, blood pressure, glucose and lipids. Whether and to what extent the excess cardiovascular risk observed in women with these pregnancy complications is explained by conventional cardiovascular risk factors (CVRFs) is not known. We examined the association between a history of SGA, LGA or preterm birth and cardiovascular disease among 23,284 parous women and quantified the contribution of individual CVRFs to the excess cardiovascular risk using an inverse odds weighting approach. The hazard ratios (HR) between SGA and LGA offspring and CVD were 1.30 (95% confidence interval (CI) 1.15, 1.48) and 0.89 (95% CI 0.76, 1.03), respectively. Smoking explained 49% and blood pressure may have explained ≈12% of the excess cardiovascular risk in women with SGA offspring. Women with preterm birth had a 24% increased risk of CVD (HR 1.24, 95% CI 1.06, 1.45), but we found no evidence for CVRFs explaining any of this excess cardiovascular risk. While smoking explains a substantial proportion of excess cardiovascular risk in women with SGA offspring and blood pressure may explain a small proportion in these women, we found no evidence that conventional CVRFs explain any of the excess cardiovascular risk in women with preterm birth.

Association of spontaneous abortion with all cause and cause specific premature mortality: prospective cohort study.

OBJECTIVE: To investigate the association of spontaneous abortion with the risk of all cause and cause specific premature mortality (death before the age of 70). DESIGN: Prospective cohort study. SETTING: The Nurses' Health Study II (1993-2017), United States. PARTICIPANTS: 101 681 ever gravid female nurses participating in the Nurses' Health Study II. MAIN OUTCOMES MEASURES: Lifetime occurrence of spontaneous abortion in pregnancies lasting less than 6 months, determined by biennial questionnaires. Hazard ratios and 95% confidence intervals for all cause and cause specific premature death according to the occurrence of spontaneous abortion, estimated with time dependent Cox proportional hazards models. RESULTS: During 24 years of follow-up, 2936 premature deaths were recorded, including 1346 deaths from cancer and 269 from cardiovascular disease. Crude all cause mortality rates were comparable for women with and without a history of spontaneous abortion (1.24 per 1000 person years in both groups) but were higher for women experiencing three or more spontaneous abortions (1.47 per 1000 person years) and for women reporting their first spontaneous abortion before the age of 24 (1.69 per 1000 person years). The corresponding age adjusted hazard ratios for all cause premature death during follow-up were 1.02 (95% confidence interval 0.94 to 1.11), 1.39 (1.03 to 1.86), and 1.27 (1.11 to 1.46), respectively. After adjusting for confounding factors and updated dietary and lifestyle factors, the occurrence of spontaneous abortion was associated with a hazard ratio of 1.19 (95% confidence interval 1.08 to 1.30) for premature mortality during follow-up. The association was stronger for recurrent spontaneous abortions (hazard ratio 1.59, 95% confidence interval 1.17 to 2.15 for three or more spontaneous abortions; 1.23, 1.00 to 1.50 for two; and 1.16, 1.05 to 1.28 for one compared with none), and for spontaneous abortions occurring early in a woman's reproductive life (1.32, 1.14 to 1.53 for age ≤23; 1.16, 1.01 to 1.33 for ages 24-29; and 1.12, 0.98 to 1.28 for age ≥30 compared with none). When cause specific mortality was evaluated, the association of spontaneous abortion with premature death was strongest for deaths from cardiovascular disease (1.48, 1.09 to 1.99). Spontaneous abortion was not related to premature death from cancer (1.08, 0.94 to 1.24). CONCLUSIONS: Spontaneous abortion was associated with an increased risk of premature mortality, particularly death from cardiovascular disease.

Hypertensive Disorders of Pregnancy and Subsequent Risk of Premature Mortality.

BACKGROUND: Hypertensive disorders of pregnancy (HDPs) are leading causes of maternal and perinatal morbidity and mortality. However, it is uncertain whether HDPs are associated with long-term risk of premature mortality (before age 70 years). OBJECTIVES: The objective of this study was to evaluate whether HDPs were associated with premature mortality. METHODS: Between 1989 and 2017, the authors followed 88,395 parous female nurses participating in the Nurses' Health Study II. The study focused on gestational hypertension and pre-eclampsia within the term HDPs. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between HDPs and premature mortality were estimated by using Cox proportional hazards models, with adjustment for relevant confounders. RESULTS: The authors documented that 2,387 women died before age 70 years, including 1,141 cancer deaths and 212 CVD deaths. The occurrence of HDPs, either gestational hypertension or pre-eclampsia, was associated with an HR of 1.31 (95% CI: 1.18 to 1.46) for premature death during follow-up. When specific causes of death were examined, these relations were strongest for CVD-related mortality (HR: 2.26; 95% CI: 1.67 to 3.07). The association between HDPs and all-cause premature death persisted, regardless of the subsequent development of chronic hypertension (HR: 1.20 [95% CI: 1.02 to 1.40] for HDPs only and HR: 2.02 [95% CI: 1.75 to 2.33] for both HDPs and subsequent chronic hypertension). CONCLUSIONS: An occurrence of HDPs, either gestational hypertension or pre-eclampsia, was associated with an increased risk of premature mortality, particularly CVD mortality, even in the absence of chronic hypertension.