N° 887

Associations Between Maternal Antenatal Corticosteroid Treatment and Mental and Behavioral Disorders in Children

Question  Is maternal antenatal corticosteroid treatment associated with mental and behavioral disorders in children?

Katri Räikkönen et al (JAMA. 2020;323(19):1924-1933. doi:10.1001/jama.2020.3937) used a population-based retrospective cohort study in Finland that included 670 097 children, exposure to maternal antenatal corticosteroid treatment, compared with nonexposure, was significantly associated with mental and behavioral disorders in children (hazard ratio, 1.33).

Meaning   These findings may help inform decisions about maternal antenatal corticosteroid treatment.

Here are some more details of the study.

Design, Setting, and Participants  Population-based retrospective cohort study using nationwide registries of all singleton live births in Finland surviving until 1 year and a within-sibpair comparison among term siblings. Children were born between January 1, 2006, and December 31, 2017, and followed up until December 31, 2017.

Exposures  Maternal antenatal corticosteroid treatment.

Main Outcomes and Measures  Primary outcome was any childhood mental and behavioral disorder diagnosed in public specialized medical care settings.

Results  Of the 674 877 singleton children born in Finland during the study period, 670 097 were eligible for analysis. The median length of follow-up was 5.8 (interquartile-range, 3.1-8.7) years. Of the 14 868 (2.22%; 46.1% female) corticosteroid treatment–exposed children, 6730 (45.27%) were born at term and 8138 (54.74%) were born preterm; of the 655 229 (97.78%; 48.9% female) nonexposed children, 634 757 (96.88%) were born at term and 20 472 (3.12%) were born preterm. Among the 241 621 eligible term-born maternal sibpairs nested within this population, 4128 (1.71%) pairs were discordant for treatment exposure. Treatment exposure, compared with nonexposure, was significantly associated with higher risk of any mental and behavioral disorder in the entire cohort of children (12.01% vs 6.45%; absolute difference, 5.56% [95% CI, 5.04%-6.19%]; adjusted hazard ratio [HR], 1.33 [95% CI, 1.26-1.41]), in term-born children (8.89% vs 6.31%; absolute difference, 2.58% [95% CI, 1.92%-3.29%]; HR, 1.47 [95% CI, 1.36-1.69]), and when sibpairs discordant for treatment exposure were compared with sibpairs concordant for nonexposure (6.56% vs 4.17% for within-sibpair differences; absolute difference, 2.40% [95% CI, 1.67%-3.21%]; HR, 1.38 [95% CI, 1.21-1.58]). In preterm-born children, the cumulative incidence rate of any mental and behavioral disorder was also significantly higher for the treatment-exposed compared with the nonexposed children, but the HR was not significant (14.59% vs 10.71%; absolute difference, 3.38% [95% CI, 2.95%-4.87%]; HR, 1.00 [95% CI, 0.92-1.09]).


N° 886

Breast Cancer Risk in Postmenopausal Women With Medical History of Thyroid Disorder in the Women’s Health Initiative

Chien-Hsiang Weng et al . (Thyroid
2020 Apr;30(4):519-530.  doi: 10.1089/thy.2019.0426. Epub 2020 Feb 3) conducted a prospective cohort study of multiethnic U.S. postmenopausal women aged 50 to 79 years enrolled in both clinical trial and observational study arms between 1993 and 1998 and followed up through February 28, 2017. Development of invasive breast cancer after enrollment was recorded and a history of hyper- or hypothyroidism before the diagnosis of breast cancer was identified. The effect modification by MHT in both study arms was analyzed. All statistical tests were two sided.

Results: Among a total of 134,122 women included in the study, 8137 participants developed invasive breast cancer during the follow-up period. There was a significant inverse association of invasive breast cancer among women with a history of hypothyroidism (hazard ratio [HR] 0.91,[95% CI] 0.86-0.97) and among women who had taken levothyroxine [HR 0.89, 95% CI 0.82-0.96]. Evaluating effect modification by MHT use, the inverse association between hypothyroidism treated with thyroid replacement medications and breast cancer risk was strongest in non-MHT users [HR 0.80, 95% CI 0.69-0.93]. The results did not significantly differ by race/ethnicity. Although a history of hyperthyroidism was associated with an increased risk of invasive breast cancer [HR 1.11, 95% CI 0.91-1.35], this finding did not reach statistical significance. They did not see significant differences in the breast cancer Surveillance, Epidemiology, and End Results stages, histologic types, morphologic grades, or receptor status (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) according to thyroid disorder status.

Conclusions: Compared with women with no history of thyroid disorder, hypothyroidism was associated with a lower risk of breast cancer. This was mainly seen among those who received thyroid replacement therapy and had never used MHT. Among the treatment options for hypothyroidism, levothyroxine had the strongest inverse association with breast cancer risk.

N° 885
Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.
Mavaddat N et al (Breast Cancer Res. 2020 Jan 16;22(1):8. doi: 10.1186/s13058-020-1247-4.) evaluated the effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers in a multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers, followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women.
There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar.
We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

N° 884
Arterial Stiffness Accelerates Within 1 Year of the Final Menstrual Period: The SWAN Heart Study.

Samargandy et al (Arterioscler Thromb Vasc Biol. 2020 Jan 23:ATVBAHA119313622. doi: 10.1161/ATVBAHA.119.313622. [Epub ahead of print]) determined whether and when women experience changes in arterial stiffness relative to the final menstrual period (FMP) and whether these changes differ between black and white midlife women studying 339 participants from the SWAN Heart Ancillary study (Study of Women’s Health Across the Nation). The interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.
Women had ≤2 carotid-femoral pulse-wave velocity (cfPWV) exams over a mean±SD of 2.3±0.5 years of follow-up. Annual percentage changes in cfPWV were estimated in 3 time segments relative to FMP and compared using piecewise linear mixed-effects models. At baseline, women were 51.1±2.8 years of age and 36% black.
Annual percentage change (95% CI) in cfPWV varied by time segments: 0.9% (-0.6% to 2.3%) for >1 year before FMP, 7.5% (4.1%-11.1%) within 1 year of FMP, and -1.0% (-2.8% to 0.8%) for >1 year after FMP. Annual percentage change in cfPWV within 1 year of FMP was significantly greater than the other 2 time segments; P<0.05 for both comparisons. Adjusting for concurrent cardiovascular disease risk factors explained part of the change estimates but did not eliminate the difference.

Black women had greater increase in cfPWV compared with white women in the first segment; P for interaction, 0.04.

The authors concluded that the interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.

N° 883
At the latest San Antonio Breast cancer symposium (December 2019, https://www.abstractsonline.com/pp8/#!/7946/presentation/2229), Chlebowski et al presented the long-term Breast cancer outcomes from the WHI Estrogen plus Progestin and Estrogen-alone trials.

During the intervention period, with 238 incident breast cancers, CEE-alone significantly reduced breast cancer incidence (HR 0.76 95%CI 0.58, 0.98, P = 0.04). As previously reported, subgroup analyses indicated CEE-alone was particularly beneficial for women with no prior HT use (interaction P = 0.04) and women with gap time >= 5 years (interaction P = 0.01). Post-intervention, through 16.1 years of cumulative follow-up, with 520 incident breast cancers, CEE-alone use continued to significantly reduce breast cancer incidence (HR 0.77 95% CI 0.65-0.92, P = 0.005) while subgroup differences were attenuated and were no longer statistically significant.

During the intervention period, with 360 incident breast cancers, CEE plus MPA use significantly increased breast cancer incidence (HR 1.26 95% CI 1.02, 1.56, P = 0.04) with increase in breast cancer incidence greater in women with prior HT use (interaction P = 0.02) and women with gap time < 5 years (interaction P = 0.002). Post-intervention, through 18.3 years cumulative follow-up, with 1,003 incident breast cancers, CEE plus MPA continued to significantly increase breast cancer incidence (HR 1.29 95% CI 1.14, 1.47, P < 0.001) while subgroup differences were attenuated and were no longer statistically significant.
The authors Conclusions: CEE-alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions: all postmenopausal women with prior hysterectomy using CEE-alone have the potential benefit of experiencing a reduction in breast cancer incidence while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence.


N° 882 Honingberg et al (JAMA. Published online November 18, 2019 doi: https://doi.org/10.1001/jama.2019.19191) reported that both premature (before 40 years) natural and surgical menopause are associated with higher incident Cardiovascular Disease (for a composite outcome that included coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism.  In a cohort study that included 144 260 postmenopausal women, For natural premature menopause, the hazard ratio was 1.36; for surgical premature menopause, the hazard ratio was 1.87.

N° 881 Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder
Kingsberg, Sheryl  et al (Obstetrics & Gynecology: November 2019 – Volume 134 – Issue 5 – p 899-908) evaluated the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder using two RCT which evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index‐desire domain score and Female Sexual Distress Scale‐Desire/Arousal/Orgasm item 13.
Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Mean age was 39 years. From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: −0.37, P<.001; study 302: −0.29, P=.005; integrated studies −0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo.
Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity.


N° 880 Discrimination, Abuse, Harassment, and Burnout in Surgical Residency Training
List of authors.
Yue-Yung Hu et al (31/10/19 N Engl J Med) conducted a cross-sectional US national survey of general surgery residents In-Training to assesse mistreatment, burnout (evaluated with the use of the modified Maslach Burnout Inventory), and suicidal thoughts during the past year. Among 7409 residents (99.3% of the eligible residents) from all 262 surgical residency programs, 31.9% reported discrimination based on their self-identified gender, 16.6% reported racial discrimination, 30.3% reported verbal or physical abuse (or both), and 10.3% reported sexual harassment.
Rates of all mistreatment measures were higher among women; 65.1% of the women reported gender discrimination and 19.9% reported sexual harassment. Patients and patients’ families were the most frequent sources of gender discrimination (as reported by 43.6% of residents) and racial discrimination (47.4%), whereas attending surgeons were the most frequent sources of sexual harassment (27.2%) and abuse (51.9%). Proportion of residents reporting mistreatment varied considerably among residency programs (e.g., ranging from 0 to 66.7% for verbal abuse).
Weekly burnout symptoms were reported by 38.5% of residents, and 4.5% reported having had suicidal thoughts during the past year. Residents who reported exposure to discrimination, abuse, or harassment at least a few times per month were more likely than residents with no reported mistreatment exposures to have symptoms of burnout (odds ratio, 2.94; 95% confidence interval [CI], 2.58 to 3.36) and suicidal thoughts (odds ratio, 3.07; 95% CI, 2.25 to 4.19). Although models that were not adjusted for mistreatment showed that women were more likely than men to report burnout symptoms (42.4% vs. 35.9%; odds ratio, 1.33; 95% CI, 1.20 to 1.48), the difference was no longer evident after the models were adjusted for mistreatment (odds ratio, 0.90; 95% CI, 0.80 to 1.00).
Mistreatment occurs frequently among general surgery residents, especially women, and is associated with burnout and suicidal thoughts.

N° 879 Trabecular Bone Score (TBS) Declines During the Menopause Transition (MT): the Study of Women’s Health Across the Nation (SWAN).
Greendale et al J Clin Endocrinol Metab. 2019 Oct 15. pii: dgz056. doi: 10.1210/clinem/dgz056. [Epub ahead of print]  used the longitudinal data from the Study of Women’s Health Across Nation to observe that the TBS during MT, beginning 1.5 years prior to the final menstrual period (FMP), declining by 1.16% annually (p<0.0001). Starting 2 years after the FMP, annual rate of TBS loss lessened to 0.89% (p<0.0001). In the 5 years before through the 5 years after the FMP, in the referent individual, total TBS decline was 6.3% (p<0.0001), but Black participants’ total TBS loss was 4.90% (p=0.0008, difference in Black and White 10-year change). Results for Japanese did not differ from those of White women.
The occurrence of an MT-related decline in TBS supports the thesis that this period is particularly damaging to skeletal integrity.