The effects of first-trimester subchorionic hematoma on pregnancy outcomes: a retrospective cohort study.

BACKGROUND: Although first-trimester subchorionic hematoma (SCH) always concerns expectant parents, its clinical significance remains controversial. This study aimed to examine the relationship between SCH and its association with subsequent miscarriage and other perinatal outcomes in singleton pregnancies. METHODS: We conducted a retrospective cohort study including 43,660 women who underwent routine prenatal care since the first trimester and then were followed up for maternal and neonatal outcomes. SCH was detected in the first-trimester ultrasound examinations. Robust Poisson regression was used to estimate adjusted risk associations of SCH with maternal and neonatal outcomes. RESULTS: A total of 815 (1.87%) SCH cases were detected in the first-trimester ultrasound examinations. The rate of miscarriage was statistically significantly higher in women with SCH than without [35.21% vs. 23.92%, P < 0.01; adjusted relative risk (RR):1.44, 95% confidence interval (CI): 1.31-1.58]. Subgroup analysis of women with SCH showed a clear trend that the earlier SCH occurred, the higher the risk of miscarriage was [adjusted RR (95% CI) for onset at the gestational weeks of 8-9, 6-7, and < 6 vs. ≥ 10: 1.30 (0.69-2.46), 2.33 (1.28-4.23), and 4.18 (2.30-7.58), respectively; Ptrend < 0.01]. In addition, women with SCH volume ≥ 1 ml showed higher risk than did those with SCH volume < 1 ml [adjusted RR (95% CI) for 1-4.9 ml, and ≥ 5 ml vs. < 1 ml: 1.36 (1.10-1.68) and 1.56 (1.18-2.07), respectively]. There was no statistically significant difference in the rates of other pregnancy outcomes between women with and without SCH. CONCLUSIONS: First-trimester SCH, particularly when characterized by early presence and large size, might significantly increase the risk of miscarriage. Data from this study suggest no associations between SCH and other maternal and neonatal outcomes.

Androgen-secreting adult granulosa cell tumor in a woman with polycystic ovary syndrome: a case report.

Aim: To present the clinicopathologic findings of the second case of androgen-secreting adult granulosa cell tumor (AGCT) in a woman with polycystic ovary syndrome (PCOS) and discuss in the light of the literature. Methods: Description of a case and discussion of the literature. Results: A patient with oligomenorrhea, amenorrhea and hirsutism who was diagnosed as PCOS and treated by oral contraceptive for three years, then left ovarian solid and liquid mass was found and pathologically confirmed to be androgen-secreting AGCT after left oophorectomy. She got regular menstrual cycle and gave birth naturally, but clinical features of PCOS reappeared after breastfeeding. Conclusion: Androgen-secreting AGCT and PCOS have similar clinical features of hyperandrogenism, it is difficult to diagnose androgen-secreting AGCT when both diseases occur in the same patient. If the size of cystic mass in androgen-secreting AGCT is too small to differentiate from PCOM on imaging, pathological examination after surgery may be the only way to find the disease.

Genomic imbalance in euploid pregnancy loss.

PURPOSE: This study aims to investigate genomic imbalance in euploid products of conceptions (POCs) detected by chromosomal microarray analysis (CMA) and its association with clinical characteristics. METHODS: In a retrospective cohort study where all women with singleton pregnancy losses underwent CMA detection of POCs, only patients with euploid POCs were included in the analysis. The clinical features were compared between those with and without a copy number variant (CNV). The pathogenic CNVs and the variant of uncertain significance (VOUS) were analyzed, and the common pathogenic CNVs and uniparental disomy (UPD) were investigated. RESULTS: A total of 610 POCs were detected as chromosomal euploid, of which 176 were euploid with CNVs and 434 were euploid without CNVs. Regarding maternal age, gestational age, and history of pregnancy loss, no significant differences were found between the two groups. Furthermore, 104 pathogenic CNVs were identified in 93 POCs, and the deletion of 8p23.3 was found in 10 subjects. All CNVs greater than 3 Mb and 39.5% of CNVs ranging from 1 to 2 Mb were pathogenic, and only 3 CNVs < 1 Mb were pathogenic. UPD was detected in 12 POCs. CONCLUSION: Besides aneuploidy, 15.24% pregnancy loss might have an association with pathogenic genomic imbalance, and the occurrence of genomic imbalance is not related to clinical characteristics. CNVs greater than 3 Mb in pregnancy losses have a high probability to be pathogenic, and approximately 40% of CNVs ranging from 1 to 2 Mb are pathogenic. The deletion of 8p23.3 is the most common pathogenic CVN in POCs of Chinese-Han women. The clinical significance of UPD in pregnancy loss needs further study.

Prepregnancy body mass index, gestational weight gain, and maternal prepartum inflammation in normal pregnancies: findings from a Chinese cohort.

BACKGROUND: Obesity has been linked to systemic inflammation in population studies. OBJECTIVE: To examine the associations of prepregnancy body mass index (pBMI) and total gestational weight gain (tGWG) with maternal prepartum low-grade inflammation (LGI) and clinically significant inflammation (CSI) defined by serum C-reactive protein (CRP) concentration. METHODS: Five thousand four hundred seventy-six Chinese women with uncomplicated pregnancies and recorded data on pBMI and prepartum body weight were included in this study. Blood samples were drawn before delivery for high-sensitivity CRP assay. Inadequate, optimal, and excessive tGWG were defined using the Institute of Medicine's recommendation. Multivariable Poisson regressions were used to estimate relative risks (RRs) for having prepartum LGI and CSI (defined as CRP concentration 3-10 and > 10 mg/L, respectively) across pBMI and tGWG categories. RESULTS: The mean pBMI, mean tGWG, and median maternal prepartum CRP concentration were 20.4 kg/m2, 13.9 kg, and 3.3 mg/L, respectively. The prevalence of prepartum CSI and LGI was 7.2% and 47.8%. The adjusted RRs (95% confidence interval) of CSI for normal (18.5-24.9 kg/m2) and high (≥ 25 kg/m2) vs. low pBMI (< 18.5 kg/m2) were 1.35 (1.05-1.74) and 2.28 (1.53-3.39), respectively. The respective adjusted RRs of LGI were 1.19 (1.11-1.28) and 1.59 (1.42-1.77). The adjusted RRs for excessive vs. optimal tGWG was 1.18 (0.94-1.48) for CSI and 1.14 (1.07-1.21) for LGI. CONCLUSIONS: Prepregnancy overweight/obesity and excessive tGWG increase the risk of maternal prepartum systemic inflammation, which further highlights the importance of weight management before and during pregnancy.

Copy Number Variation Analysis of Euploid Pregnancy Loss.

Objectives: Copy number variant (CNV) is believed to be the potential genetic cause of pregnancy loss. However, CNVs less than 3 Mb in euploid products of conceptions (POCs) remain largely unexplored. The aim of this study was to investigate the features of CNVs less than 3 Mb in POCs and their potential clinical significance in pregnancy loss/fetal death. Methods: CNV data were extracted from a cohort in our institution and 19 peer-reviewed publications, and only those CNVs less than 3 Mb detected in euploid pregnancy loss/fetal death were included. We conducted a CNV map to analyze the distribution of CNVs in chromosomes using R packages karyoploteR_1.10.5. Gene names and annotated gene types covered by those CNVs were mined from the human Release 19 reference genome file and GENECODE database. We assessed the expression patterns and the consequences of murine knock-out of those genes using TiGER and Mouse Genome Informatics (MGI) databases. Functional enrichment and pathway analysis for genes in CNVs were performed using clusterProfiler V3.12.0. Result: Breakpoints of 564 CNVs less than 3 Mb were obtained from 442 euploid POCs, with 349 gains and 185 losses. The CNV map showed that CNVs were distributed in all chromosomes, with the highest frequency detected in chromosome 22 and the lowest frequency in chromosome Y, and CNVs showed a higher density in the pericentromeric and sub-telomeric regions. A total of 5,414 genes mined from the CNV regions (CNVRs), Gene Ontology (GO), and pathway analysis showed that the genes were significantly enriched in multiple terms, especially in sensory perception, membrane region, and tight junction. A total of 995 protein-coding genes have been reported to present mammalian phenotypes in MGI, and 276 of them lead to embryonic lethality or abnormal embryo/placenta in knock-out mouse models. CNV located at 19p13.3 was the most common CNV of all POCs. Conclusion: CNVs less than 3 Mb in euploid POCs distribute unevenly in all chromosomes, and a higher density was seen in the pericentromeric and sub-telomeric regions. The genes in those CNVRs are significantly enriched in biological processes and pathways that are important to embryonic/fetal development. CNV in 19p13.3 and the variations of ARID3A and FSTL3 might contribute to pregnancy loss.

Residual risk associations between initial hyperglycemia and adverse pregnancy outcomes in a large cohort including 6709 women with gestational diabetes.

AIMS: To estimate the residual risk associations between hyperglycemia and adverse pregnancy outcomes after glycemia-controlling intervention. METHODS: Among 41,067 Chinese women, those with gestational diabetes mellitus (GDM), according to the IADPSG criteria, received standard interventions to control glycemia. Risk associations of plasma glucose (PG) levels with excess newborn birth weight, primary cesarean section, and preterm delivery were estimated and compared with those in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, where hyperglycemia was left untreated. RESULTS: A total of 6,709 (16.3%) women developed GDM and thus received predominantly lifestyle interventions. The incidence of excess newborn birth weight, primary cesarean section, and preterm delivery was 6.1%, 19.1%, and 4.0%, respectively. Higher fasting and higher post-load PG levels during 75-g oral glucose tolerance test (OGTT) were statistically significantly associated with increased risks of excess newborn birth weight and pre-term delivery. Compared with the HAPO study, the association of fasting PG level with excess newborn birth weight showed similar strength and dose-response pattern, contrasting with considerably weakened associations for post-load PG levels that involved glycemic control. Contrary risk associations were seen across GDM subtypes compared with non-GDM, isolated fasting GDM was associated with increased, whereas isolated post-load GDM was associated with decreased, risks of excess newborn birth weight and primary cesarean section. Limiting the analysis to non-GDM women and GDM women with low HbA1c (<6.0%) ≥30 days after interventions overall attenuated the risk associations. CONCLUSIONS: Residual risk associations exist between hyperglycemia and adverse pregnancy outcomes despite seemingly appropriate glycemic control.

Chromosomal Aneuploidy Associated With Clinical Characteristics of Pregnancy Loss.

OBJECTIVE: Embryonic aneuploidy is found in about half of sporadic pregnancy losses and the associations between the chromosomal aneuploidy and clinical characteristics of pregnancy loss remain unclear. The aims of this study were to evaluate the associations between chromosomal aneuploidy of products of conception (POC) and clinical features of pregnancy loss. METHODS: We conducted a retrospective cohort study including 1,102 women experienced singleton pregnancy loss and underwent chromosomal microarray analysis (CMA) detection of POC in our hospital. The results of molecular karyotypes and clinical features including maternal age, history of pregnancy loss, gestational age, vaginal bleeding and ultrasonographic findings were extracted from the medical records. χ2 test was used to compare categorical data between groups. RESULTS: 631 (57.26%) POC specimens were detected to be chromosomal aneuploidy. Aneuploid rates were significantly higher in women >35 years (P < 0.001) and pregnancy loss <11 gestational weeks (P = 0.044), but the rates of sex chromosome abnormalities and triploid were significantly higher in women ≤35 years (P < 0.001, P = 0.002) and the rates of viable autosomal trisomy and sex chromosome abnormalities were significantly high in those women with pregnancy loss ≥11 weeks (P < 0.001, P < 0.001). Aneuploid rate was overall similar between the sporadic and the recurrent pregnancy loss (RPL) (P = 0.404), but the rate of sex chromosome abnormalities was higher in women with sporadic pregnancy loss (P = 0.03). Aneuploid rates were higher in subjects with yolk sac or embryo than in those without (P < 0.001 and P = 0.001). CONCLUSION: Advanced maternal age is mainly associated with autosomal trisomy, while sex chromosome abnormalities and triploid might be more likely to occur in younger women. Aneuploidy rates might be no association with previous pregnancy loss except for sex chromosome abnormalities. Pregnancy loss without yolk sac or embryo might be less related to embryonic aneuploidy, and other factors should be emphasized.

[Mutation analysis of a family affected with isolated proteinuria].

OBJECTIVE: To analyze the clinical characteristics and genetic features of a family affected with isolated proteinuria. METHODS: Clinical data of the family was collected. Mutations of 191 renal disease-related genes in the proband were screened with next generation sequencing (NGS). Sanger sequencing was used to verify suspected mutations in his family members and 100 healthy controls. The impact of the mutation was predicted with online software SIFT. Frequency of the mutation was searched in databases including 1000 Genomic Project, ESP and ExAC. RESULTS: NGS and Sanger sequencing showed that the proband harbored compound heterozygous mutations of ADCK4 gene including c.748C>G (p.Asp250His) and c.1041G>T (p.Cys347*), which were respectively inherited from his mother and father whom were both non-symptomatic. CONCLUSION: The proband may have ADCK4-associated glomerulopathy due to the compound heterozygous mutations of the ADCK4 gene.

Decreased Plasma COMP and Increased Plasma CTX-II Levels in a Chinese Pseudoachondroplasia Family with Novel COMP Mutation.

Pseudoachondroplasia (PSACH) is an autosomal dominant osteochondrodysplasia caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Accurate clinical diagnosis of PSACH is sometimes difficult. Here, we identified a novel COMP mutation (c.1675G>A, p.Glu559Lys) in a Chinese PSACH family. We detected the plasma levels of COMP and type II collagen (CTX-II) in the four affected individuals. The results showed the levels of plasma COMP significantly decreased and plasma CTX-II significantly increased in the three PSACH patients with COMP mutation. However, both plasma levels of COMP and CTX-II were not to have found significant difference between the presymptomatic carrier and the age-matched subjects. In vitro analysis and immunofluorescence displayed wild type COMP homogenously expressed in cytoplasm, but mutant proteins were irregularly accumulated inside the HEK-293 cells. Western blot revealed that the quantity of the mutant COMP was more compared to wild type COMP in cells after transfection for 12 hours and 24 hours. Subsequently, 3D structural analysis showed three changes have taken place in secondary structure of the mutant COMP. In conclusion, the novel mutation of COMP may result in intracellular accumulation of the mutant protein. Decreased plasma COMP and increased plasma CTX-II may potentially serve as diagnostic markers of PSACH but may not be applicable in the presymptomatic carrier.

Congenital adrenal hyperplasia due to 11-hydroxylase deficiency-Compound heterozygous mutations of a prevalent and two novel CYP11B1 mutations.

11ß-hydroxylase deficiency (11ß-OHD) occurs in about 5-8% of congenital adrenal hyperplasia (CAH). In this study, we identified three CYP11B1 (encoding Cytochrome P450 11B1) heterozygous mutations: c.1358G>C (p.R453Q), c.1229T>G (p.L410R) and c.1231G>T (p.G411C) in a Chinese CAH patient due to classic 11ß-OHD. His parents were healthy and respectively carried the prevalent mutation c.1358G>C (p.R453Q), and the two novel mutations c.1229T>G (p.L410R) and c.1231G>T (p.G411C). In vitro expression studies, immunofluorescence demonstrated that wild type and mutant (L410R and G411C) proteins of CYP11B1 were correctly expressed on the mitochondria, and enzyme activity assay revealed the mutant reduced the 11-hydroxylase activity to 10% (P<0.001) for the conversion of 11ß-deoxycortisol to cortisol. Subsequently, three dimensional homology models for the normal and mutant proteins were built by using the x-ray structure of the human CYP11B2 as a template. Interestingly, in the heme binding site I helix, a change from helix to loop in four amino acide took place in the mutant model. In conclusion, this study expands the spectrum of mutations in CYP11B1 causing to 11ß-OHD and provides evidence for prenatal diagnosis and genetic counseling. In addition, our results confirm the two novel CYP11B1 mutations led to impaired 11-hydroxylase activity in vitro.

Association of interleukin-10 gene promoter polymorphisms with recurrent pregnancy loss: a meta-analysis.

PURPOSE: It has been reported single-nucleotide polymorphisms (SNPs) of the IL-10 promoter might be associated with the susceptibility to recurrent pregnancy loss (RPL). Owing to the inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the IL-10 promoter SNPs and RPL risk. METHODS: A systematic search of studies on the association of the three SNPs with RPL was conducted in PubMed and Embase. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to pool the effect size. RESULT: Eleven case-control studies on rs1800896, seven studies on rs1800871, and eight studies on rs1800872 were included. A significant association was identified between IL-10 rs1800896 with RPL risk (G versus A: OR = 1.21, 95 % CI 1.09-1.35). No evidence of association was found between rs1800871 and RPL when restricted to those studies in Hardy-Weinberg equilibrium in controls (T versus C: OR = 1.25, 95 % CI 0.76-2.06). No statistical association was demonstrated between rs1800872 and RPL (C versus A: OR = 1.08, 95 % CI 0.83-1.42). CONCLUSIONS: IL-10 rs1800896 significantly increases the risk of RPL, while rs1800872 is not correlated with RPL risk. No significant association is demonstrated between rs1800871 and RPL risk but this requires further investigation.