Concordant and Discordant Transcriptomic Signatures of Twin Placentas in the Setting of Preeclampsia.

BACKGROUND

Multifetal pregnancies have increased preeclampsia risk, but the underlying pathogenesis may differ from that of singletons. It remains unclear whether twin placentas show molecular signs of preeclampsia synchronously.

METHODS

We performed RNA sequencing on 32 individual placental samples from twin gestations grouped by preeclampsia status: 24 dichorionic twin (DT) and 8 monochorionic twin gestations. Ten singleton placentas from preeclamptic pregnancies were also analyzed. A benchmark data set (GSE203507, GSE114691, and GSE1482410) and a test data set (GSE190973) comprised 71 early onset preeclampsia and 69 control singleton placentas. Differential abundance analysis was conducted, and machine learning was used to derive a novel 98-transcript classification signature (accuracy >0.97 in benchmark and test data sets).

RESULTS

Across 7 groups, 2946 transcripts were differentially modulated (likelihood-ratio test; false discovery rate <0.05). Placental signature scoring distinguished normotensive from early onset preeclampsia in GSE203507 singletons (P<0.0001) although normotensive DTs did not differ from DTs with preeclampsia (Kruskal-Wallis/Dunn). Notably, some twin placentas without clinical preeclampsia exhibited preeclampsia-like profiles. Linear mixed-effects regression, which accounted for intertwin correlation structure, revealed increasing signature scores across singleton and DT groups (all P<0.01): normotensive singletons<normotensive DT<DT with preeclampsia<singletons with preeclampsia. Functional analysis in twins showed preeclampsia-like dysregulation but with pronounced variability. Intertwin divergence was more prominent in DT than in monochorionic twin samples, regardless of clinical diagnosis.

CONCLUSIONS

These findings highlight the complexity of preeclampsia pathology in twins. In DT pregnancies complicated by preeclampsia, placental involvement may be asymmetrical, suggesting that disease may arise from a single affected placenta; however, these results require replication.