Ting Peng

The effects of thyroid hormone replacement or suppression therapy in women with thyroid cancer on thyroid function during pregnancy and subsequent adverse fetal outcomes are still largely unknown. To compare thyroid function at 8 weeks of gestation and its changes during pregnancy between the survivors and controls, and to assess the association of these differences with adverse fetal outcomes. This was a retrospective cohort-based parallel control study. A total of 140 survivors and 280 controls delivery time-matched controls were extracted from 46,610 singleton pregnant women who received prenatal examinations in a second-level specialized hospital between January 2019 and March 2024. The primary outcomes were birth defects, small for gestational age (SGA, defined as birth weight < 10th percentile by gestational week), preterm birth (< 37 weeks), and neonatal asphyxia (defined as fetuses with a 1 min-Apgar score of < 7). Apgar scores at 1 and 5 min and umbilical arterial blood gas (ABG) indexes were surrogate indicators of neonatal asphyxia. Compared to the control group, FT3 was lower in the survivors, while FT4 was higher. Change of FT3 between 8 and 16 weeks of gestation in survivors was significantly smaller than that in the controls (-0.08 vs. -0.30, P < 0.005). The survivors had an insignificant association with SGA/preterm birth (adjusted OR 2.06, 0.68-6.23, P = 0.20), a slightly higher risk of fetal asphyxia (Peto OR, 6.49; 95% CI: 0.81-52.0; P = 0.078), and a lower 1 min Apgar score (β, -0.10; 95% CI: -0.16 to -0.03;P = 0.004). Change in FT3 between 8 and 16 weeks was associated with SGA/preterm birth (adjusted OR, 4.42, 95%CI: 1.32-14.84, P = 0.016). FT3 at 8 weeks of gestation and its changes between 16 and 32 weeks of gestation were negatively correlated with the umbilical ABG index, with both β of -0.02(p = 0.015 and 0.019, respectively). This study found differences in FT3 and FT4 levels and their changes during pregnancy between the survivors and controls. These differences, especially the changes in FT3 during pregnancy, might suggest a potential biological link, though further studies are needed to establish causality.

Introduction: Dramatic alterations of the extracellular matrix (ECM), which can regulate cell behavior by binding to adhesion molecules and are intrinsically linked to immune regulation, occur in decidualization during early pregnancy. Decidual macrophages (dMφ) are a group of tissue-resident cells with an affinity for adhesion. An interactive dialogue occurs between decidual stromal cells (DSCs) and dMφ, however it remains unclear whether this process is associated with ECM-adhesion molecules. This study was conducted to investigate the cross-talk of DSC and CD16 ⁺ dMφ via extracellular matrix-adhesion molecule interaction in early pregnancy. Methods: Single-cell sequencing data from endometrial and decidual tissues were analyzed to elucidate the interactions between DSCs and dMφ. We assessed the levels of ECM components in the decidua at the tissue or cellular levels, and examined the expression of adhesion molecules and polarization molecules in CD16 ⁺ or CD16 ^- dMφ. Then we validated DSC-CD16 ⁺ Mφ interactions using the co-culture system. Finally, we evaluated the levels of ECM components in decidua and the expression of molecules in dMφ in patients with recurrent miscarriage (RM). Results: DSCs communicated with dMφ via ECM-adhesion molecules. Collagen IV, osteopontin (OPN) and hyaluronic acid (HA) derived from DSCs promoted the development of CD16 ⁺ dMφ and their differentiation toward an immunomodulatory phenotype via their receptors, which is beneficial for maintaining immune tolerance. In patients with RM, decidua exhibits weakened ECM-CD16 ⁺ dMφ regulatory link, which may be associated with the underlying pathogenesis. Discussion: This study confirms that DSC can regulate the immune status of CD16 ⁺ dMφ through the ECM-adhesion molecule axis, further elucidating the regulatory mechanisms of Mφ during decidualization. Exploration of therapeutic strategies based on ECM-receptor-mediated stroma-immune interactions holds promise as novel treatment approaches for miscarriage.

Purpose: This study aimed to reveal the interrelationships among vaginal microorganisms, metabolism, and inflammatory factors in premature pregnant women.Methods: A total of 77 pregnant women were enrolled and divided into a preterm birth group (n = 23) and a full-term birth group (n = 54) according to the gestational week of delivery. Blood samples and vaginal secretion samples were collected before the onset of labor or after rupture of membranes for blood index testing, 16S RNA sequencing of vaginal secretion samples, and untargeted metabolite determination.Results: Compared with the full-term group, the preterm group exhibited significantly elevated inflammatory markers (SII 689 vs. 1,061, p < 0.001) and decreased vaginal microbiota α diversity (Shannon index 3.56 vs. 2.65). Meanwhile, the abundance of Firmicutes was increased (54.96% vs. 76.73%), primarily comprising Lactobacillus jensenii, which was negatively correlated with gestational week; metabolomics identified 83 significantly differential metabolites, including upregulated tyrosine-arginine, cholesterol sulfate, and benzene compounds such as 2,4-dichlorophenol. KEGG analysis revealed that pathways such as kynurenine, steroids, lipids, and microbial metabolism were significantly activated in the preterm birth group. Omics association analysis revealed significant correlations among microbiota, metabolites, and inflammatory markers. For example, Lactobacillus jensenii and inflammatory metabolites such as arginine-lysine, sulfamethoxazole, 5-aminovaleric acid, and epoxiconazole were all positively correlated with SII (p < 0.05).Conclusion: The results suggest that an imbalance in vaginal microbiota, particularly the abnormal proliferation of Lactobacillus jensenii, as well as amino acid and lipid metabolism may be associated with inflammation-induced preterm birth.

The establishment and maintenance of pregnancy encompass a series of complex and high-energy-consuming physiological processes, resulting in a significant energy demand. Fatty acids, one of the most essential nutrients, play a crucial role in energy supply via oxidation and perform critical biological functions such as anti-inflammatory and anti-oxidant effects, which substantially impact human health. Disordered fatty acid metabolism can cause anomalies in fetal growth and development, as well as a range of pregnancy problems, which can influence the health of both the mother and the fetus. In this review, we innovatively explore the relationship between fatty acid metabolism abnormalities and pregnancy complications, emphasizing the potential of dietary interventions with polyunsaturated fatty acids in improving pregnancy outcomes. These findings provide important evidence for clinical interventions and enhance the understanding and practical application of health management during pregnancy.

Persistent and intense uterine contraction is a risk factor for preterm labor. We previously found that methyl-CpG-binding protein 2 (MeCP2), as a target of infection-related microRNA miR-212-3p, may play an inhibitory role in regulating myometrium contraction. However, the molecular mechanisms by which MeCP2 regulates myometrial contraction are still unknown. In this study, we found that MeCP2 protein expression was lower in myometrial specimens obtained from preterm labor cases, compared to those obtained from term labor cases. Herein, using RNA sequence analysis of global gene expression in human uterine smooth muscle cells (HUSMCs) following siMeCP2, we show that MeCP2 silencing caused dysregulation of the cholesterol metabolism pathway. Notably, MeCP2 silencing resulted in the upregulation of CYP27A1, the key enzyme involved in regulating cholesterol homeostasis, in HUSMCs. Methylation-specific PCR, chromatin immunoprecipitation, and dual luciferase reporter gene technology indicated that MeCP2 could bind to the methylated CYP27A1 promoter region and repress its transcription. Administration of siCYP27A1 in a lipopolysaccharide (LPS)-induced preterm labor mouse model delayed the onset of preterm labor. Human preterm myometrium and the LPS-induced preterm labor mouse model both showed lower expression of MeCP2 and increased expression of CYP27A1. These results demonstrated that aberrant upregulation of CYP27A1 induced by MeCP2 silencing is one of the mechanisms facilitating inappropriate myometrial contraction. CYP27A1 could be exploited as a novel therapeutic target for preterm birth.

Prokineticin 1 (PROK1) is a secreted protein involved in a range of physiological activities such as cell proliferation, migration, angiogenesis, and neuronal cell proliferation. Emerging evidences show that PROK1/PROK receptors (PROKRs) are expressed by trophoblasts, and decidual stroma cells at the maternal-fetal interface. PROK1 plays a critical role in successful pregnancy establishment by regulating the decidualization, implantation and placental development. Dysregulation of prokineticin signaling has been described in certain pathological states associated with pregnancy, including pre-eclampsia, recurrent miscarriage and fetal growth restriction. In this review, the expression and pleiotropic roles of PROK1 under physiological and pathological pregnancy conditions are discussed.

Background: Folic acid (FA) supplementation is associated with a lower risk of the neural tube and heart defects and is recommended for women of childbearing age. Although there are detailed recommendations, differences in the initiation time and duration of FA supplementation remain poorly studied. Methods: A multicentre prospective study of 17,713 women was conducted. The incidence of congenital malformations in women taking a recommended dosage (e.g. 0.4 or 0.8 mg/day) of FA was compared with that in women without supplementation. The predicted probability of malformations by the initiation time and duration of FA use was estimated to determine optimal options. Results: Periconceptional FA supplementation was associated with a lower and insignificant risk of congenital malformations (1.59% vs. 2.37%; odds ratio [OR] 0.69; 95% confidence interval [CI]: 0.44–1.08), heart defects (3.8 vs. 8.0 per 1000 infants; OR, 0.47; 0.21–1.02), and neural tube defects (7.0 vs. 11.5 per 10,000 infants; OR, 0.64; 0.08–5.15). FA use after pregnancy provided greater protection against total malformations. Statistically significant associations were found in women who initiated FA supplementation in the first month of gestation (OR, 0.55; 95% CI: 0.33–0.91) and in those who supplemented for 1 to 2 months (OR, 0.59; 95% CI: 0.36–0.98). Similar results were found for heart defects. The optimal initiation time was 1.5 (optimal range: 1.1 to 1.9) months before pregnancy and a duration of 4.0 (3.7 to 4.4) months was reasonable to achieve the lowest risk of congenital malformations. Heart defect prevention required an earlier initiation (2.2 vs. 1.1 months before pregnancy) and a longer duration (4.7 vs. 3.7 months) than the prevention of other malformations. Conclusions: The timely initiation of FA supplementation for gestation was associated with a decreased risk of congenital malformations, which was mainly attributed to its protection against heart defects. The initiation of FA supplementation 1.5 months before conception with a duration of 4 months is the preferred option for congenital malformation prevention. Trial registration: Chictr.org.cn identifier: ChiCTR-SOC-17010976.

Background: Assisted reproductive technology (ART) is generally safe, but still associated with risks of various adverse maternal and neonatal outcomes.Methods: This retrospective cohort study included all deliveries (through either ART or unassisted pregnancy) during a period from January 5th, 2015 to September 30th, 2020 at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. A propensity score-matched (PSM) analysis was conducted to compare adverse maternal and neonatal outcomes between ART and unassisted pregnancy. The PSM was performed at a 1:4 ratio using a caliper width that equals to 0.02 of the standard deviation of the propensity score logit. The results are presented as relative risk (RR) and 95% confidence interval (95%CI).Results: We screened a total of 78,022 deliveries: 4,310 (5.5%) through ART and the remaining 73,712 (94.5%) through unassisted pregnancy. The ART group had older age (33.2±3.9 vs 30.4±4.0 years), higher rate of cesarean section (70.2% vs 38.1%) and multiple pregnancies (23.6% vs 1.7%). In the PSM analysis (4,218 and 15,003 deliveries, respectively), the ART group had higher risks of preeclampsia (10.5% vs 5.7%, RR: 1.57, 95%CI: 1.44-1.71), gestational diabetes mellitus (19.5% vs 16.0%, RR: 1.27, 95%CI: 1.16-1.38) and placenta-related diseases, including placenta previa (2.7% vs 1.8%, RR: 1.52, 95% CI: 1.21-1.89), placenta accreta spectrum (6.8% vs 3.0%, RR: 1.95, 95%CI: 1.72-2.22) and abnormal placental morphology (8.4% vs 5.5%, RR: 1.22, 95%CI: 1.14-1.30). In singletons, the ART group had higher risks of large-for-gestational-age (LGA) (13.7% vs 10.2%, RR: 1.40, 95%CI: 1.25-1.57) and stillbirth (0.3% vs 0.1%, RR: 2.24, 95% CI: 1.25-4.03) but lower risk of small-for-gestational-age (SGA) (4.2% vs 5.4%, RR: 0.84, 95%CI: 0.73-0.97). In multiple births, the ART group had lower risks of SGA (13.4% vs 17.8%, RR:0.83, 95%CI: 0.74-0.93), preterm birth (44.8% vs 59.2%, RR: 0.56, 95%CI: 0.49-0.64) and stillbirth (0.1% vs 0.6%, RR: 0.42, 95%CI: 0.20-0.90). Analysis of the overall, pre-matching study population yielded largely similar findings.Conclusion: Pregnancy through ART was associated with higher risks of most maternal outcomes. Interestingly, the risks of neonatal outcomes differed between singleton and multiple birth groups.

Background. Evidence for the association between maternal thyroxine concentration and the risk of fetal congenital heart defects (CHDs) is absent. We aimed to study the association of maternal free and total thyroxine (FT4 and TT4) concentrations and the free-to-total thyroxine proportion (FTT4P, ) with the risk of CHD. Methods. The study was a hospital-based cohort study of 52,047 women who received a universal thyroid function test between 2012 and 2016. CHD was screened by ultrasound between 20 and 24 weeks of gestation or diagnosed until the 42^nd day of birth. Adjusted odds ratios (ORs) of fetal CHD were estimated for maternal FT4 and TT4 concentrations or the FTT4P by multivariate logistic regression. Results. A total of 41,647 women with singleton pregnancies were included for the analysis and 215 CHD cases were detected. The FT4 concentration was significantly associated with a higher risk of CHDs (OR, 1.04, 95 confidence interval (CI): 1.01 to 1.07). Each 1 higher FTT4P was related to a 1.41-fold (95 CI: 0.27 to 3.59) higher risk of CHDs. The association became stronger for women with a thyroid function test performed between 12 and 18 weeks of gestation (OR=1.05 (95 CI: 1.01 to 1.09) for the FT4 concentration and 3.32 (95 CI: 1.43 to 7.73) for the FTT4P). Conclusions. A higher FT4 concentration or FTT4P, measured between 12 and 18 weeks of gestation, was associated with an increased risk of CHDs. These findings may provide new insights into the mechanisms of CHDs and evidence for clinical decisions related to thyroid function tests.

Mol Hum Reprod. 2019;25:274–282