The Proteome Landscape of Human Placentas for Monochorionic Twins with Selective Intrauterine Growth Restriction.

In perinatal medicine, intrauterine growth restriction (IUGR) is one of the greatest challenges. The etiology of IUGR is multifactorial, but most cases are thought to arise from placental insufficiency. However, identifying the placental cause of IUGR can be difficult due to numerous confounding factors. Selective IUGR (sIUGR) would be a good model to investigate how impaired placentation affects fetal development, as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors. Herein, we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins. Specifically, we identified a total of 5481 proteins, of which 233 were differentially expressed (57 up-regulated and 176 down-regulated) in IUGR twins. Bioinformatics analysis indicates that these differentially expressed proteins (DEPs) are mainly associated with cardiovascular system development and function, organismal survival, and organismal development. Notably, 34 DEPs are significantly enriched in angiogenesis, and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed. Moreover, we found decreased expression of metadherin (MTDH) in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro. Collectively, our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins, and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.

Serum hsCRP in early pregnancy and preterm delivery in twin gestations: a prospective cohort study.

BACKGROUND: Systemic inflammation during pregnancy may be associated with preterm delivery (PTD), but data for twin gestations are lacking. The aim of this study was to examine the association of serum high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, in early pregnancy of twin gestations with risk of PTD, including spontaneous (sPTD) and medical-induced preterm delivery (mPTD). METHODS: A prospective cohort study involved 618 twin gestations was conducted in a tertiary hospital in Beijing, from 2017 to 2020. Serum samples collected in early pregnancy were analyzed for hsCRP using particle-enhanced immunoturbidimetric method. Unadjusted and adjusted geometric means (GM) of hsCRP were estimated using linear regression, and compared between PTD before 37 weeks of gestation and term delivery at 37 or more weeks of gestation using Mann-Whitney rank sum test. The association between hsCRP tertiles and PTDs was estimated using logistic regression, and further converted overestimated odds ratios into relative risks (RR). RESULTS: A total of 302 (48.87%) women were classified as PTD, with 166 sPTD and 136 mPTD. The adjusted GM of serum hsCRP was higher in PTDs (2.13 mg/L, 95% confidence interval [CI] 2.09 -2.16) compared to term deliveries (1.84 mg/L, 95% CI 1.80 -1.88) (P < 0.001). Compared with the lowest tertile of hsCRP, the highest tertile was associated with increased risk of PTD (adjusted relative risks [ARR] 1.42; 95% CI: 1.08-1.78). Among twin pregnancies, the adjusted association between high values of serum hsCRP in early pregnancy and preterm delivery was only observed in the subgroup of spontaneous preterm deliveries (ARR 1.49, 95%CI:1.08-1.93). CONCLUSIONS: Elevated hsCRP in early pregnancy was associated with increased risk of PTD, particular the risk of sPTD in twin gestations.

Statistical Approach to Decreasing the Error Rate of Noninvasive Prenatal Aneuploid Detection caused by Maternal Copy Number Variation.

Analyses of cell-free fetal DNA (cff-DNA) from maternal plasma using massively parallel sequencing enable the noninvasive detection of feto-placental chromosome aneuploidy; this technique has been widely used in clinics worldwide. Noninvasive prenatal tests (NIPT) based on cff-DNA have achieved very high accuracy; however, they suffer from maternal copy-number variations (CNV) that may cause false positives and false negatives. In this study, we developed an algorithm to exclude the effect of maternal CNV and refined the Z-score that is used to determine fetal aneuploidy. The simulation results showed that the algorithm is robust against variations of fetal concentration and maternal CNV size. We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio. A total of 6615 pregnant women were enrolled in a prospective study to validate the accuracy of our method. All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%. In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach.

[Research of placental vascular distribution and clinical outcome in monochorionic twins].

OBJECTIVE: To study the placental vascular distribution of monochorionic (MC) twins with twin-to-twin transfusion syndrome (TTTS) or birth weight discordance. METHODS: Twenty-eight MC placentas were injected in Peking University Third Hospital between Feb. 2010 and Feb. 2011. The vascular distribution type (parallel, crossed, mixed and monoamniotic), the anastomosis of vessels and the placental sharing were recorded. The outcome of pregnancy and the placental characteristics of birth weight discordance (birth weight discordance≥20%) in non-TTTS MC twins were analyzed. RESULTS: (1) The outcome of pregnancy: the miscarriage or gestational weeks of 28 MC twins were 20 to 38 weeks (median of 35 weeks). Six cases were TTTS, 3 of which received fetoscopic laser occlusion of communicating vessels (FLOC). There were 48 live births, with an average birth weight of (2036±623) g. (2) Type of placental vascular distribution:in the 28 MC placentas, number of parallel, crossed, mixed and monoamniotic type of placental vascular distribution were 4 (14%), 14 (50%), 6 (21%) and 4 (14%) cases, respectively. No parallel type was found in TTTS. There was no significant difference of vascular anastomosis or unequal placental sharing among the different placental vascular distribution types (P>0.05). (3) Characteristics of placental vascular distribution in birth weight discordance twins:there were 20 non-TTTS MC twin pregnancies, all of which got live births of both babies. Birth weight discordance equal to or more than 20% was found in 6 pairs of newborns, while birth weight discordance less than 20% was found in the rest 14 cases. Ratio of unequal placental sharing was significantly different between the two groups (P<0.01). There was no significant difference of umbilical cord insertion, placental vascular distribution and anastomosis in the two groups (P>0.01). CONCLUSIONS: Vascular distribution type of MC twins might be related to TTTS. Unequal placental sharing is a risk factor of birth weight discordance in non-TTTS MC twins.

[Umbilical cord ligation in the fetocide of complicated monochorionic multiple gestations].

OBJECTIVE: To evaluate the clinical effect and safety of umbilical cord ligation in the fetocide of complicated monochorionic multiple gestations. METHODS: From January 2009 to December 2012, clinical data of 18 women with complicated monochorionic multiple gestations who experienced intrauterine percutaneous umbilical cord ligation in Peking University Third Hospital were collected. Among the patients, 6 were selective intrauterine growth restriction (1 with type I, 4 with type II, 1 with type III); 4 were acrania or hydropic twins; 4 were acardiac twins, 2 were complicated triplet gestation; 1 was twin-twin transfusion syndrome with right ventricular dysplasia and 1 was monochorionic diamniotic (MCDA) with caesarean section history. The procedure was performed under both endoscopic and sonographic guidance. The gestational age at the time of the procedure were 17-27(+6) weeks. The procedure and perinatal outcome were analyzed. RESULTS: (1) The procedure was performed successfully in all the 18 cases. The average duration of the procedure was 63 min (24-156 min). The blood loss was 7.6 ml (5-20 ml). The mean gestational age at the time of the procedure was 20 weeks (17-27(+) weeks). The average birth weight of the neonates was 2441 g (1000-3400 g) .(2) There were 206 fetuses survived. Two fetuses had cardiac anomalies and were terminated in the following 2-3 weeks.Intrauterus fetal demise occured in 3 twin reverse arterial perfusion syndrome (TRAP) cases 3-14 weeks after the procedure.1 case delivered as early preterm birth at 28 weeks and the neonate died of respiratory distress syndrome (RDS) and hypoxie-ischemicen-cephalopathy (HIE) .Fourteen neonates were in healthy and normal development by 3-51 months' follow-up.(3) Fourteen cases delivered at more than 28 weeks (28-38 weeks, averagely 33(+1) weeks). The gestational weeks were prolonged by 5-21 weeks (averagely 13(+4) weeks). Among them, 3 case were early preterm birth (28-33 weeks) and 3 were late preterm birth (34-36 weeks). CONCLUSION: Percutaneous umbilical cord ligation is a reliable technique for the fetocide of complicated monochrionic mutilple gestations, especially for monochronic monoamniotic pregnancies.

[Expressions of HIF-α and its target gene in monochorionic twin placentas with twin-twin transfusion syndrome].

OBJECTIVE: To determine hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF) and receptor (VEGFR-1) concentrations in the placentas of the donor and recipient in monochorionic twin pregnancies with twin-twin transfusion syndrome (TTTS). METHODS: Twenty monochorionic twin pregnancy cases were included in the study (10 with and 10 without TTTS). Tissue protein expressions of HIF-1α,VEGF and VEGFR-1 were determined by using immunohistochemistry. Western blot analysis were used to quantify and compare the protein expression. RT-PCR were used to compare their mRNA expressions. RESULTS: HIF-1α was mainly observed in trophoblastic cells and villi capillaries endothelial cells, and VEGF in trophoblastic cells, endothelial cells and villi stromal cells; VEGFR-1 was mainly observed in villi trophoblastic cells and vascular endothelial cells. The placenta protein and mRNA expression of HIF-1α and its target gene in the donor placenta increased significantly (P<0.001) compared with that in the control placenta, but the expression of HIF-1α and its target gene in the recipients tended to be similar in the controls (P>0.05). There was no difference between the controls. CONCLUSION: When the monochorionic twin placenta is formed in the early period, HIF-1α, VEGF and VEGFR-1 are over-expressed, which may affect the placenta angiogenesis and induce TTTS .