Huidong Zhang

Background: Heat exposure is associated with adverse pregnancy outcomes, but previous reviews have not systematically examined temporal trends or critical exposure windows, and several outcomes remain unpooled.Methods: We conducted a systematic review and meta-analysis of population-based observational studies on ambient temperature and adverse maternal-fetal outcomes. This review was registered on PROSPERO (CRD420251048362). We searched databases up to August 2026 and included 214 studies covering 18 outcomes across at least 34 countries; more than half were published between 2023 and 2026. We assessed study risk of bias developed by the World Health Organization, used random-effects models, time-stratified analyses, gestational window analyses, trim-and-fill tests, and GRADE.Findings: Heat exposure was associated with increased risks of preterm birth (OR 1.11 for short-term exposure; OR 1.35 for third-trimester exposure), stillbirth (OR 1.42), pre-eclampsia (OR 1.65), gestational diabetes (OR 1.33), birth defects (OR 1.38 for heatwaves), and small-for-gestational-age (OR 1.10). Associations with preterm birth and small-for-gestational-age strengthened over time, and the third trimester was the most susceptible window for preterm birth. Certainty of evidence was moderate for most outcomes and low for small-for-gestational-age.Interpretation: These findings carry direct implications for public health policy and clinical practice. Heat-related pregnancy risks are not static and have intensified in recent years, with late pregnancy emerging as a high-priority window for preventive intervention. Our pooled estimates also provide quantitative evidence for outcomes that were previously unexamined in meta-analyses. Urgent priorities for climate adaptation and maternal health policy include integrating pregnant women into heat-health action plans, enhancing prenatal counselling and surveillance, and protecting pregnant people in low-resource settings.

The global accumulation of nanoplastics poses wide concerns for human health. Although their toxicity in various organs is being uncovered, their impact on vaginal microbiomes that are essential for healthy reproduction remains largely unknown. Here, we discover a previously unrecognized long-term nanoplastic reproductive toxicity that prepregnant exposure to high doses of aged polystyrene nanoparticles (aPS-NPs) induces mouse miscarriage and restricts embryo development by persistently causing vaginal microbial dysbiosis (an increase in Aerococcus urinae abundance), vaginal glutamine depletion (suppression of Slc1a5-mediated import of glutamine from outside cells to intracells), and vaginal inflammation (up-regulation of Ifnar1, Il-1β, and Il-18) from prepregnancy to pregnancy, despite the fact that aPS-NPs are almost undetectable in the vagina on D14 in pregnancy. Transplant of A. urinae into the vaginal tract exacerbates these processes and adverse pregnancy outcomes. Interventions, such as Slc1a5 overexpression, glutamine supplement, or anti-inflammatory treatment, can effectively recover these processes and alleviate the adverse outcomes. Therefore, this study not only demonstrates a previously unrecognized long-term nanoplastic reproductive toxicity by persistently causing vaginal dysbiosis, metabolic dysfunctions, and inflammation, ultimately inducing adverse pregnant outcomes, but also provides experimental basis for targeted therapies to combat the escalating threat of nanoplastic pollution.

Background: Extreme heat driven by climate change has become a growing threat to reproductive health. Existing systematic studies are limited to only a few adverse pregnancy outcomes, with limited evidence, inconsistent regional findings, and insufficient comprehensive synthesis across multiple pregnancy complications. Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library from database inception to March 2026. Eligible observational studies reporting quantitative effect estimates linking heat exposure to any of the six predefined outcomes were included. Pooled effect sizes were synthesized using random-effects models. Subgroup and sensitivity analyses were conducted to explore heterogeneity and robustness. Funnel plots and Egger’s test were used to assess publication bias. An adapted Intergovernmental Panel on Climate Change (IPCC) framework was applied to rate the certainty of evidence. Findings: Overall, 95 studies covering 51 countries and 376,093,515 births were included. Heat exposure was significantly associated with all six placenta-originated adverse pregnancy outcomes: preterm birth (OR, 1.23; 95% CI, 1.20-1.27), stillbirth (OR, 1.60; 95% CI, 1.41-1.80), low birth weight (OR, 1.26; 95% CI, 1.13-1.41), birth defects (OR, 1.09; 95% CI, 1.05-1.13), pre-eclampsia (OR, 2.21; 95% CI, 2.03-2.41), and miscarriage (OR, 1.22; 95% CI, 1.12-1.32). Pre-eclampsia showed the strongest association with heat exposure. All outcomes had high between-study heterogeneity (I² > 85%), and leave-one-out sensitivity analyses confirmed stable pooled estimates. Subgroup analyses by actual observation period revealed distinct temporal trends for preterm birth and stillbirth. An unexpected higher pre-eclampsia risk was observed in high-income populations. We further rated evidence certainty via an adapted IPCC framework, with confidence levels ranging from very high for preterm birth to low for birth defects. Interpretation: Global heat exposure significantly elevates the risk of a broad spectrum of placenta-originated adverse pregnancy outcomes, with pre-eclampsia showing the strongest association magnitude. These findings underscore the urgent need for targeted clinical counseling and public health heat-protection strategies to safeguard pregnant women with ongoing global climate warming.

The pathogenesis of unexplained miscarriage (UM) is largely unclear. Environmental Zn pollution is widely present in various environments and inevitably ingested by pregnant women, which has shown reproductive toxicity. Disulfidptosis is a newly identified programmed cell death caused by excessive disulfide stress. Notably, the association, causation, and underlying mechanisms among Zn exposure, disulfidptosis, and unexplained miscarriage are completely unknown. In this study, based on two UM case‐control groups, four ZnCl ₂ ‐exposed mouse models, and a ZnCl ₂ ‐exposed trophoblast Swan 71 cell model, we obtain a consistent conclusion that excessive Zn exposure causes disulfidptosis and thus induces miscarriage by up‐regulating the GATA1/METTL1/SLC7A11 axis. In the mechanism, Zn exposure up‐regulates GATA1 expression levels, which promotes GATA1‐mediated METTL1 and SLC7A11 transcription. Meanwhile, Zn exposure also promotes METTL1‐mediated m7G modification on SLC7A11 mRNA and thus increases SLC7A11 mRNA stability. Ultimately, Zn exposure up‐regulates SLC7A11 expression levels at both transcription and post‐transcription levels and thus causes disulfidptosis. Knockdown of murine Slc7a11, Gata1, or Mettl1, or supplement with NADPH suppresses mouse placental disulfidptosis and alleviates mouse miscarriage. This study not only discovers pathogenesis and biological mechanisms of Zn exposure‐induced unexplained miscarriage but also provides potential targets, uncovering new health risk effects of Zn exposure in the environment‐health field.

High incidence of unexplained miscarriage (UM) limits global human reproduction. Lithium (Li) batteries are widely used but rarely recycled, causing Li to spread into environments and enter human body. Notably, the healthy effects of Li exposure on UM are rarely explored. Herein, higher serum Li levels, villous tissue ferroptosis, and UM are associated. Exposure to high levels of Li causes placental ferroptosis to induce mouse miscarriage. Li exposure down-regulates ER levels to suppress ER-mediated METTL1 and MBOAT1 transcription, and also suppresses METTL1-mediated m7G modification on MBOAT1 mRNA to reduce MBOAT1 mRNA stability. Therefore, Li exposure causes ferroptosis in a GPX4-independent manner. Supplement with murine Mboat1 suppresses placental ferroptosis and relieves miscarriage in LiCl-exposed mouse model. This study discovers health risks and pathogenesis of Li exposure-induced UM, reveals potential biological targets, and also proposes an important Li exposure theme in energy-environment-health field, which deserves attention by global governments and enterprises.

Unexplained miscarriage (UM) remains challenge due to unclear pathogenesis and biological mechanisms. BPB (Bisphenol B), an extensively used endocrine disrupting chemical, has been widely detected out in human. Migrasomes are newly identified cellular organelles with a large number of unknown functions. However, whether and how BPB exposure may suppress migrasome formation (MF) to induce miscarriage are completely unknown. In this study, it is found that higher urinary BPB levels are associated with the suppressed MF in villous tissues and unexplained miscarriage. It is further confirmed that BPB exposure suppresses MF in the mouse placenta and thus induces miscarriage. Supplement with Pkca or Tspan4, two essential proteins for migration/invasion (MI) and MF, can efficiently treat against BPB‐induced miscarriage. In biological mechanisms, BPB up‐regulates ER levels, enhances its interactions with the lnc‐HZ04 promoter region, and thus promotes ER‐mediated lnc‐HZ04 transcription. Subsequently, lnc‐HZ04 suppresses TCF4‐mediated PKCA transcription and subsequently suppresses MI and MF. Collectively, this study not only identifies BPB as a novel risk factor for unexplained miscarriage, discovers novel pathogenesis and biological mechanisms in BPB‐induced miscarriage, but also provides potential targets for treatment against unexplained miscarriage.

High incidence of recurrent miscarriage (RM, recurrent abnormal early embryo loss) largely limits global human reproduction. However, it is unclear how the pathogenesis greatly restricts its effective clinical treatment. In our previous studies, we have identified a group of novel long non-coding RNAs (lncRNAs), which might regulate the occurrence of RM through unknown biological mechanisms. In this study, we confirm that a novel lncRNA, lnc-HZ14, which is highly expressed in unexplained RM vs healthy control (HC) villous tissues, is associated with RM using a new RM case-control group (n = 50). In trophoblast cellular assays, lnc-HZ14 suppresses trophoblast cell proliferation by specifically downregulating SPHK1 (sphingosine kinase 1) protein levels. In terms of mechanism, lnc-HZ14 upregulates SQSTM1/p62 protein levels, enhances its protein interactions with polyubiquitin-modified SPHK1, promotes the formation of SQSTM1-SPHK1 bodies through liquid-liquid phase separation (LLPS), and accelerates SPHK1 aggrephagy degradation. Meanwhile, lnc-HZ14 also promotes autophagy by activating ETV4-mediated transcription of ATG101 and PPP1R15A/GADD34. The cellular mechanisms are consistent with those in villous tissues of RM patients and in placental tissues of a mouse miscarriage model, excepting that there is no lnc-HZ14 homolog in mouse. As for miscarriage treatment, therapeutic upregulation of SPHK1 by treatment with phorbol 12-myristate 13-acetate (PMA), an SPHK1 agonist recovers mouse placental proliferation and alleviates mouse miscarriage. Collectively, this study shows for the first time the regulatory roles of lnc-HZ14, LLPS, and aggrephagy degradation of SPHK1 in unexplained recurrent miscarriage, uncovering novel pathogenesis and biological mechanisms of unexplained RM and also providing potential targets for treatment against miscarriage.