Meta-analysis examining fetal sex-specific placental DNA methylation intensities and estimated cell composition post IVF
Bibliographic record
Abstract
Infertility impacts up to 17.5% of reproductive-aged couples worldwide. To aid in conception, many couples turn to ART, such as IVF. IVF can introduce both physical and environmental stressors that may alter DNA methylation regulation, an important and dynamic process during early fetal development. This meta-analysis aims to assess the differences in the placental DNA methylome between spontaneous and IVF pregnancies. Potential datasets were identified by searching the NCBI Gene Expression Omnibus (GEO) using keywords related to IVF in human participant studies published before November 2023. In our combined fetal sex population (N = 575) from three eligible GEO datasets, 127 autosomal cytosine guanine dinucleotides (CpGs) were significant (False Discovery Rate (FDR) <0.05) between IVF (n = 96) and spontaneous (n = 479) placentae, with 47 CpGs considered differentially methylated (FDR < 0.05 and |Δβ| > 0.05). Stratification by fetal sex revealed no significant autosomal CpGs in fetal female placentae (N = 281); however, in the fetal male placentae (N = 294), we identified nine autosomal CpGs that reached statistical significance between IVF (n = 56) and spontaneous (n = 238) placentae, with three CpGs considered differentially methylated. Fetal male placentae had lower proportions of trophoblasts (P < 0.0001) and stromal cells (P = 0.007) and higher proportions of syncytiotrophoblasts (P = 0.0001) compared to fetal female placentae, regardless of conception type. IVF placentae had higher proportions of stromal cells (P = 0.01) and lower proportions of syncytiotrophoblasts (P = 0.01) compared to spontaneous placentae, regardless of sex. Controlling for cell-type proportions in linear models reduced test statistic inflation and identified new significant CpGs that may previously have been masked by cell-type heterogeneity. The results of this meta-analysis are critical to further understand the impact of IVF on tissue epigenetics, which may help with understanding the connections between IVF and negative pregnancy outcomes. Additionally, our study suggests that sex-specific differences in placental DNA methylation and cell composition should be considered as factors for future placental DNA methylation analyses.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".