Association of maternal mild hypothyroidism in the first and third trimesters with obstetric and perinatal outcomes: a prospective cohort study.

BACKGROUND: Mild hypothyroidism, including subclinical hypothyroidism and isolated maternal hypothyroxinemia, is fairly common in pregnant women, but its impact on pregnancy outcomes is less clear, especially mild hypothyroidism in late pregnancy. OBJECTIVE: To evaluate the impact of subclinical hypothyroidism and isolated maternal hypothyroxinemia in the first and third trimesters, respectively, on obstetric and perinatal outcomes. STUDY DESIGN: This large prospective study was conducted at the International Peace Maternity and Child Health Hospital in Shanghai; 52,027 pregnant women who underwent the first-trimester antenatal screening at International Peace Maternity and Child Health Hospital were consecutively enrolled from January 2013 to December 2016. To evaluate the impact of maternal subclinical hypothyroidism and isolated maternal hypothyroxinemia in the first trimester on pregnancy outcomes, participants were divided into 3 groups according to thyroid function in the first trimester: first-trimester euthyroidism group (n=33,130), first-trimester subclinical hypothyroidism group (n=884), and first-trimester isolated maternal hypothyroxinemia group (n=846). Then, to evaluate the impact of maternal subclinical hypothyroidism and isolated maternal hypothyroxinemia in the third trimester on pregnancy outcomes, the first-trimester euthyroidism group was subdivided into 3 groups according to thyroid function in the third trimester: third-trimester euthyroidism group (n=30,776), third-trimester subclinical hypothyroidism group (n=562), and third-trimester isolated maternal hypothyroxinemia group (n=578). Obstetric and perinatal outcomes, including preterm birth, preeclampsia, gestational hypertension, gestational diabetes mellitus, large for gestational age, small for gestational age, macrosomia, cesarean delivery, and fetal demise were measured and compared between those in either subclinical hypothyroidism/isolated maternal hypothyroxinemia group and euthyroid group. Binary logistic regression was used to assess the association of subclinical hypothyroidism or isolated maternal hypothyroxinemia with these outcomes. RESULTS: Thirty-four thousand eight hundred sixty pregnant women who had first (weeks 8-14) and third trimester (weeks 30-35) thyrotropin and free thyroxine concentrations available were included in the final analysis. Maternal subclinical hypothyroidism in the first trimester was linked to a lower risk of gestational diabetes mellitus (adjusted odds ratio 0.64, 95% confidence interval 0.50-0.82) compared with the euthyroid group. However, third-trimester subclinical hypothyroidism is associated with heightened rates of preterm birth (adjusted odds ratio 1.56, 95% confidence interval 1.10-2.20), preeclampsia (adjusted odds ratio 2.23, 95% confidence interval 1.44-3.45), and fetal demise (adjusted odds ratio 7.00, 95% confidence interval 2.07-23.66) compared with the euthyroid group. Isolated maternal hypothyroxinemia in the first trimester increased risks of preeclampsia (adjusted odds ratio 2.14, 95% confidence interval 1.53-3.02), gestational diabetes mellitus (adjusted odds ratio 1.45, 95% confidence interval 1.21-1.73), large for gestational age (adjusted odds ratio 1.64, 95% confidence interval 1.41-1.91), macrosomia (adjusted odds ratio 1.85, 95% confidence interval 1.49-2.31), and cesarean delivery (adjusted odds ratio 1.35, 95% confidence interval 1.06-1.74), while isolated maternal hypothyroxinemia in the third trimester increased risks of preeclampsia (adjusted odds ratio 2.85, 95% confidence interval 1.97-4.12), large for gestational age (adjusted odds ratio 1.49, 95% confidence interval 1.23-1.81), and macrosomia (adjusted odds ratio 1.60, 95% confidence interval 1.20-2.13) compared with the euthyroid group. CONCLUSION: This study indicates that while first-trimester subclinical hypothyroidism did not elevate the risk for adverse pregnancy outcomes, third-trimester subclinical hypothyroidism was linked to several adverse pregnancy outcomes. Isolated maternal hypothyroxinemia in the first and third trimesters was associated with adverse pregnancy outcomes, yet the impact varied by trimester. These results suggest the timing of mild hypothyroidism in pregnancy may be pivotal in determining its effects on adverse pregnancy outcomes and underscore the importance of trimester-specific evaluations of thyroid function.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes.

BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

Metabolome implies increased fatty acid utilization and histone methylation in the follicles from hyperandrogenic PCOS women.

Well-balanced metabolism is essential for the high-quality of oocytes, and metabolic fluctuations of follicular microenvironment potentially encourage functional changes in follicle cells, ultimately impacting the developmental potential of oocytes. Here, the global metabolomic profiles of follicular fluid from PCOS women with ovarian hyperandrogenism and nonhyperandrogenism were depicted by untargeted metabolome and transcriptome. In parallel, functional methods were employed to evaluate the possible impact of dysregulated metabolites on oocyte and embryo development. Our findings demonstrated that PCOS women exhibited distinct metabolic features in follicles, such as the increase in fatty acid utilization and the downregulation in amino acid metabolism. And intrafollicular androgen levels were positively correlated with contents of multiple fatty acids, suggesting androgen as one of the contributing factors to the metabolic abnormalities in PCOS follicles. Moreover, we further demonstrated that elevated levels of α-linolenic acid and H3K27me3 could hinder oocyte maturation, fertilization, and early embryo development. Hopefully, our data serve as a broad resource on the metabolic abnormalities of PCOS follicles, and advances in the relevant knowledge will allow the identification of biomarkers that predict the progression of PCOS and its poor pregnancy outcomes.

Sexual behavior and cardiovascular diseases: univariable and multivariable Mendelian randomization.

Background: To assess the relationship of genetically predicted sexual behavior (age at first sex (AFS) and the number of sexual partners (NSP)) on cardiovascular diseases (CVDs). Methods and results: We performed two-sample Mendelian randomization (MR) with publicly available datasets from the UK Biobank and FinnGen Study, and analyzed genome-wide association results for sexual behaviors and twelve types of CVDs. The univariable MR method provided a total effect of AFS and NSP on CVDs, and showed evidence that early AFS rather than NSP was associated with CVDs, including angina pectoris (AP), atrial fibrillation and flutter (AFF), coronary atherosclerosis (CAS), deep vein thrombosis of the lower extremity (DVT-LE), heart failure (HF), hypertension (HTN), ischaemic stroke (IS), and myocardial infarction (MI). Given sex as a social determinant of CVD risk, we used gender-stratified SNPs to investigate gender differences in the development of CVDs. These results showed a stronger causal relationship of AFS on CVDs in females than in males. Further multivariable MR analyses indicated a direct effect after accounting for insomnia, number of days of vigorous physical activity 10 + minutes (VPA 10 + min), and time spent watching television (TV). Two-step MR demonstrated these three risk factors act as a mediator in AFS associated AP/HTN/HF. Conclusions: We provide evidence that early AFS increased the risk of CVDs. These associations may be partly caused by VPA 10 + min, insomnia, and the time spent on TV. The causality of AFS on CVDs in females was stronger than in males. Conversely, genetically predicted NSP was not associated with CVDs.

The causal association between smoking initiation, alcohol and coffee consumption, and women's reproductive health: A two-sample Mendelian randomization analysis.

Objective: A number of epidemiological studies have demonstrated that smoking initiation and alcohol and coffee consumption were closely related to women's reproductive health. However, there was still insufficient evidence supporting their direct causality effect. Methods: We utilized two-sample Mendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between smoking initiation, alcohol and coffee consumption, and women's reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-PRESSO, MR-Egger, weighted median, and weighted mode to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. Results: We found evidence that smoking women showed a significant inverse causal association with the sex hormone-binding globulin (SHBG) levels (corrected ß = -0.033, p = 9.05E-06) and age at menopause (corrected ß = -0.477, p = 6.60E-09) and a potential positive correlation with the total testosterone (TT) levels (corrected ß = 0.033, p = 1.01E-02). In addition, there was suggestive evidence for the alcohol drinking effect on the elevated TT levels (corrected ß = 0.117, p = 5.93E-03) and earlier age at menopause (corrected ß = -0.502, p = 4.14E-02) among women, while coffee consumption might decrease the female SHBG levels (corrected ß = -0.034, p = 1.33E-03). Conclusion: Our findings suggested that smoking in women significantly decreased their SHBG concentration, promoted earlier menopause, and possibly reduced the TT levels. Alcohol drinking had a potential effect on female higher TT levels and earlier menopause, while coffee consumption might lead to lower female SHBG levels.

Comparative effectiveness of three treatment options for slade and dodds grade III-IV scaphoid nonunion: a retrospective study.

OBJECTIVE: To compare the clinical efficacy of open debridement screw fixation combined with bone grafting, percutaneous screw fixation, and percutaneous screw fixation combined with injection of platelet-rich plasma (PRP) for the treatment of Slade and Dodds Grade III to IV scaphoid nonunion (SNU). METHODS: This retrospective study included patients with Grade III (25 patients) and Grade IV (28 patients) SNU. They were treated with open surgery bone grafting and internal fixation (group A), percutaneous screw fixation (group B) or percutaneous screw fixation and PRP injection (group C) from January 2015 to May 2020. The fracture consolidation rate, VAS score, and Mayo wrist function score were compared across the three groups. RESULTS: The consolidation rate was not significantly different among the three groups for both Grade III and IV SNU. However, patients in group C reported significantly less pain and better wrist function 7 days after surgery compared to group A and B, for both nonunion grades. At 3 months after surgery, group C had significantly better VAS and Mayo wrist scores compared to group A for both nonunion grades, and compared to group B for Grade IV SNU. At 6 and 12 months after surgery, patients with Grade IV SNU in groups A and C had significantly better VAS and Mayo wrist scores compared to group B. CONCLUSION: This study suggests that percutaneous screw fixation with PRP injection could be a more effective method for treating Grade IV SNU. This approach may reduce postoperative wrist pain and improve wrist function in the early stages after surgery for patients with both Grade III and IV SNU. TYPE OF STUDY/LEVEL OF EVIDENCE: IV.

The Causal Evidence of Birth Weight and Female-Related Traits and Diseases: A Two-Sample Mendelian Randomization Analysis.

Objectives : A large meta-analysis indicated a more pronounced association between lower birth weight (BW) and diseases in women but less concern about the causality between BW and female-related phenotypes and diseases. Methods: Mendelian randomization (MR) analysis was used to estimate the causal relationship between two traits or diseases using summary datasets from genome-wide association studies. Exposure instrumental variables are variants that are strongly associated with traits and are tested using four different statistical methods, including the inverse variance weighting, MR-Egger, weighted median, and weighted mode in MR analysis. Next, sensitivity analysis and horizontal pleiotropy were assessed using leave-one-out and MR-PRESSO packages. Results: The body mass index (BMI) in adulthood was determined by BW (corrected ß = 0.071, p = 3.19E-03). Lower BW could decrease the adult sex hormone-binding globulin (SHBG) level (ß = -0.081, p = 2.08E-06), but it resulted in increased levels of bioavailable testosterone (bio-T) (ß = 0.105, p = 1.25E-05). A potential inverse effect was observed between BW and menarche (corrected ß = -0.048, p = 4.75E-03), and no causal association was confirmed between BW and the risk of endometriosis, leiomyoma, and polycystic ovary syndrome. Conclusion: Our results suggest that BW may play an important role and demonstrates a significant direct influence on female BMI, SHBG and bio-T levels, and menarche.

High-intensity focused ultrasound in the management of adenomyosis: long-term results from a single center.

OBJECTIVE: To investigate the long-term clinical outcomes of patients with adenomyosis treated by high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: From June 2012 to January 2020, 2311 patients with adenomyosis were treated with HIFU at our center, 1982 patients who have complete clinical data were retrospectively reviewed. Among the patients who completed the follow-up, 485 were treated with HIFU alone, 289 were treated with HIFU followed by GnRH-a, 255 were treated with HIFU combined with Mirena and 594 were treated with HIFU combined with GnRH-a and Mirena. The dysmenorrhea severity pain score and average menorrhagia severity score before and at 3 months, 6 months, 1 year, 2 years, 3 years and 5 years after HIFU were compared. The adverse effects were recorded. In addition, the efficacy between patients treated with GnRH-a and/or Mirena were compared. RESULTS: After HIFU ablation, the dysmenorrhea severity pain score and the menorrhagia severity score were significantly decreased at each follow-up time point. However, it was observed that as the follow-up time increased, the effective rate of HIFU treatment in improving dysmenorrhea and menorrhagia decreased. The 6 months and 3 years follow-up results showed that the efficacy of HIFU combined with Mirena and HIFU combined with GnRH-a and Mirena were significantly higher than HIFU alone and HIFU combined with GnRH-a (p < 0.05). The major complications were rare. CONCLUSION: HIFU is a safe and effective treatment for patients with adenomyosis. HIFU combined with Mirena or HIFU combined with GnRH-a and Mirena can significantly enhance the long-term treatment results.

A comparative analysis of pregnancy outcomes of patients with uterine fibroids after high intensity focused ultrasound ablation and laparoscopic myomectomy: a retrospective study.

PURPOSE: The aim of this study was to retrospectively compare and analyze pregnancy outcomes of patients with uterine fibroids after high intensity focused ultrasound (HIFU) ablation and laparoscopic myomectomy (LM). MATERIALS AND METHODS: The study group consisted of 346 patients with uterine fibroids who wished to conceive, in which 152 patients received HIFU ablation treatment (HIFU group) and 194 patients received LM treatment (LM group). The parents' baseline characters were recorded and the pregnancy outcomes were evaluated in a median follow-up time of 42 months (range: 16 ∼ 81) after the treatment, and the differences of the two groups were compared. RESULTS: Patients with uterine fibroids in HIFU group had a significant shorter pregnancy interval than that in LM group (10 months VS. 13 months, p < .05). No significant differences were observed in pregnancy rate, miscarriage rate, live birth rate, natural pregnancy rate, cesarean section rate, and perinatal complications rate between the HIFU group and the LM group (p > .05). When stratified by age, infertility history, fibroid types, fibroid numbers, and fibroid sizes, there was no statistically significant difference in pregnancy rate between the HIFU group and the LM group (p > .05). CONCLUSIONS: Based on the results from this study, both HIFU and LM can be safely used to treat patients who wish to conceive. The pregnancy outcomes of post-HIFU are similar to that of post-LM.

Long-term follow-up outcome and reintervention analysis of ultrasound-guided high intensity focused ultrasound treatment for uterine fibroids.

OBJECTIVE: To investigate the long-term reintervention of ultrasound-guided high intensity focused ultrasound (USgHIFU) treatment for uterine fibroids and analyze the factors affecting reintervention rate after USgHIFU. MATERIALS AND METHODS: Three hundred and eight-one patients with uterine fibroids treated by USgHIFU at the third Xiangya Hospital of Central South University from April 2012 to December 2014 were retrospectively reviewed. The factors that affect the reintervention rate were analyzed. RESULTS: The mean follow-up time was 70.0 ± 9.0 months. During the follow-up period, 86.4% (329/381) of the patients reported symptomatic relief and the fibroids shrank after USgHIFU treatment. Seventy-nine patients received reintervention included myomectomy, a second session of HIFU, and hysterectomy. The overall reintervention rate was 20.7% (79/381). The reasons for reintervention included symptomatic recurrence in 50 (50/79, 63.3%) patients, psychological factors in 14 (14/79, 17.7%) patients, fertility requirement in three (3/79, 3.8%) patients, suspected uterine sarcoma in two (2/79, 2.5%) patients and others in 10 (10/79, 12.7%) patients. The reintervention rate has significant correlation with some factors including age, size, type and the signal intensity on T2 weighted image (T2WI) of the uterine fibroids. CONCLUSION: USgHIFU for uterine fibroids is effective due to low reintervention rate in a long-term follow-up.

Serum and peritoneal fluid levels of interleukin-6 and interleukin-37 as biomarkers for endometriosis.

This study aimed to compare the levels of interleukin (IL)-1ß, IL-6, IL-10, and IL-37 in the serum and peritoneal fluid of women with and without endometriosis. In addition, it aimed to determine the diagnostic values of the cytokines with significantly different concentrations. The levels of IL-1ß, IL-6, IL-10, and IL-37 in the serum and peritoneal fluid samples of 40 women with endometriosis and 32 women without endometriosis were measured using an enzyme-linked immunosorbent assay. The serum and peritoneal fluid levels of IL-1ß and IL-10 were not statistically significantly different between the endometriosis and control groups. The IL-6 and IL-37 levels in the serum and peritoneal fluid were higher in the endometriosis group than in the control group, and they were correlated with the stage of endometriosis. The AUC for the IL-37 was 0.897 for the serum and 0.934 for the peritoneal fluid, while the AUC for the IL-6 was 0.905 for the serum and 0.952 for the peritoneal fluid. Our results suggest that the serum and peritoneal fluid IL-6 and IL-37 levels were significantly increased in the endometriosis patients, indicating that these cytokines may serve as biomarkers for the diagnosis of endometriosis.

IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways.

Endometriosis (EMs) is a chronic inflammatory condition. Interleukin (IL)-37 is a member of the IL-1 family and an anti-inflammatory cytokine. This study aimed to evaluate the possible role of IL-37 in the EMs pathogenesis. We investigated the in vivo effect of IL-37 on EMs by injection with recombinant human IL-37 (rhIL-37) into EMs mice. Furthermore, we evaluated the in vitro effects of IL-37 on proliferation, adhesion, migration and invasiveness of endometrial stromal cells (ESCs), and explored whether Wnt/ß-catenin and mitogen-activated protein kinase (MAPK) pathways were involved in this process. In cultured ESCs, IL-37 overexpression significantly suppressed both protein and mRNA expression of the inflammation-associated cytokines, including IL-1ß, IL-6, IL-10 and tumor necrosis factor (TNF-α). Furthermore, IL-37 overexpression significantly inhibited ESCs proliferation, adhesion, migration, invasion and the activity of matrix metalloproteinase (MMP)-2 and MMP-9. In contrast, knockdown of IL-37 exerted the opposite effects. Importantly, the IL-37-mediated action in ESCs was through inactivation of Wnt/ß-catenin, p38 MAPK, extracellular signal-related kinases MAPK and c-Jun N-terminal kinase MAPK pathways. Moreover, EMs mice treated with rhIL-37 showed the decreased endometriotic-like lesion size and lesion weight, lower expression of IL-1ß, IL-6, IL-10, TNF-α, vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-I (ICAM-I) and MMP-2/9 activity in peritoneal fluid compared with the wide type (WT) EMs mice. These findings suggest that IL-37 suppresses cell proliferation, adhesion, migration and invasion of human ESCs through multiple signaling pathways, thereby affecting the occurrence and development of EMs.