Epigenetic regulation is an important entry point to study the pathogenesis of selective fetal growth restriction (sFGR), and an understanding of the role of long noncoding RNAs (lncRNAs) in sFGR is lacking. Our study aimed to investigate the potential role of a lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), in sFGR using molecular biology experiments and gain- or loss-of-function assays. We found that the levels of MALAT1, ERRγ, and HSD17B1 were downregulated and that of miR-424 was upregulated in the placental shares of the smaller twins. Moreover, angiogenesis was impaired in the placental share of the smaller fetus and MALAT1 could regulate the paracrine effects of trophoblasts on endothelium angiogenesis and proliferation by regulating miR-424. In trophoblasts, MALAT1 could competitively bind to miR-424 to regulate the expression of ERRγ and HSD17B1, thus regulating trophoblast invasion and migration. MALAT1 overexpression could decrease apoptosis and promote proliferation, alleviating cell damage induced by hypoxia. Taken together, the downregulation of MALAT1 can reduce the expression of ERRγ and HSD17B1 by competitively binding to miR-424, impairing the proangiogenic effect of trophoblasts, trophoblast invasion and migration, and the ability of trophoblasts to compensate for hypoxia, which may be involved in the pathogenesis of sFGR through various aspects.

OBJECTIVE: To determine whether it is the magnitude of early postnatal catch-up growth (CUG) in response to fetal growth restriction (FGR) or the FGR itself that negatively impacts cognitive outcome in a model of monochorionic twins discordant for fetal growth.
METHODS: This analysis is part of the LEMON study, a cohort study including all monochorionic twins with selective FGR aged 3 through 17 years. Growth measurements as documented by our primary care system were collected retrospectively. An age-appropriate neurodevelopmental test was performed generating a full-scale IQ (FSIQ). CUG at 2 years was calculated as (weight [kg] at 2 years-birth weight [kg]). We used a multivariable regression model investigating the association between FSIQ (outcome) and birth weight zscore, gestational age at birth and CUG at 2 years (predictors). Generalized estimating equations accounted for the fact that observations between cotwins are not independent.
RESULTS: Median age at follow-up of the 46 included twin pairs was 11 (IQR 8-13) years. Birth weight z score and gestational age at birth were significantly associated with FSIQ, with β-coefficients of 5.897 (95% CI 3.382-8.411), and 2.589 (95% CI 1.227-3.951), respectively (P < .0001). Adjusted for birth weight z score and gestational age, CUG in the first 2 years after birth was not significantly associated with FSIQ (β-coefficient 0.108 [95% CI -1.373 to 1.590], P = .886).
CONCLUSIONS: Our results, combining detailed growth measurements and neurodevelopmental follow-up in a discordant identical twin model, demonstrate that FGR itself rather than early postnatal CUG has negative consequences for cognitive development.

Monochorionic twins are at risk for complications due to the presence of placental vascular anastomoses, including twin-twin transfusion syndrome, twin anemia-polycythemia sequence, selective fetal growth restriction, and twin reversed arterial perfusion sequence. While ultrasound is the primary modality to screen for the development of these complications, MRI plays an important role in assessing monochorionic twin pregnancies for the development of other complications, such as neurologic injury. In this article, the authors review the ultrasound imaging findings associated with monochorionic twin complications, management options, and the role for MRI in these pregnancies.

OBJECTIVE: Monochorionic twins (MC) have higher risk of perinatal morbi-mortality compared to singletons and dichorionic twins (DC). Selective fetal growth restriction (sFGR) increases the chances of adverse outcome. Hepatic arterial buffer response (HABR) is an important mechanism for maintaining liver perfusion. We hypothesised that HABR is active in monochorionic diamniotic twins (MCDA) with sFGR where restricted fetus may have liver hypoperfusion. The objective of this study is to test whether the HAV-ratio is diminished in pregnancies affected by selective fetal growth restriction pointing to activation of HABR in the growth-restricted fetus.
METHODS: sFGR was defined according to a consensus definition. Hepatic artery (HA) peak systolic velocity (PSV) was measured and its correlation with fetal Dopplers and pregnancy characteristics were determined. A ratio using HA-PSV (HAV-ratio) was calculated and its association with sFGR was established. Further analysis of HA-PSV was performed comparing z-scores between normal and growth restricted fetuses.
RESULTS: We included 202 MCDA pregnancies, 160 (79 %) normal and 42 (21 %) with sFGR. HAV-ratio was significant different between groups. The mean HAV-ratio was 1.01 (±0.20) for normal twins and 0.77 (±0.25) for sFGR. Furthermore, HA-PSV z-scores was significant increased in in growth-restricted fetus (0.94±1.45), while in normal fetuses was -0.16 (±0.97).
CONCLUSIONS: Our findings demonstrate that, in pregnancies with sFGR, HAV-ratio is significantly lower than in normal MCDA pregnancies. The lower HAV-ratio is due to an increase in HA PSV in the growth restricted fetus. This observation indicates an activation of HABR in the small fetus.

Background: Most previous studies evaluated outcomes of twin-twin transfusion syndrome (TTTS) without considering the coexistence of selective fetal growth restriction (sFGR). The objectives of this study were to compare twin survival and pregnancy complications after laser therapy of TTTS with and without sFGR. Methods: For this purpose, a retrospective cohort study including 98 monochorionic diamniotic twins and three dichorionic triamniotic triplets treated in a single tertiary center was conducted. Results: Overall, 46 twins had selective fetal growth restriction (26 type I, 13 type II, 7 type III). At birth, donor survival (61% vs. 91%), double survival (57% vs. 82%), and overall survival (75% vs. 88%) were significantly lower in the group with coexistent sFGR. Recipient survival (89% vs. 86%), miscarriage (7% vs. 2%), PPROM < 32 weeks (48% vs. 29%), and preterm delivery < 32 weeks (52% vs. 45%) were not significantly higher in the group with coexistent sFGR. Donor twins with sFGR type I (69% vs. 91%) and types II-III (50% vs. 91%) showed significantly lower survival than those without sFGR. Multivariate regression analysis identified sFGR and its subtypes as independent predictors of donor demise. Conclusions: the coexistence of sFGR in TTTS pregnancies was associated with poor donor outcomes and is probably the most important predictor of donor survival.

UNASSIGNED: Fetal growth restriction (FGR) can negatively affect lung development, leading to increased respiratory morbidity and reduced lung function later in life. Studies regarding the impact of FGR on lung function in singletons are influenced by genetic, obstetric, and maternal factors. To overcome these confounding factors, we aim to investigate lung function in identical twins with selective FGR (sFGR).
UNASSIGNED: Lung function assessments were performed in identical twins with sFGR born in our centre between March 1, 2002, and December 31, 2017, aged between 5 and 17 years. sFGR was defined as birthweight discordance ≥20%. Outcome measures consisted of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and transfer factor for carbon monoxide (DLCO) and were compared between the smaller and larger twin.
UNASSIGNED: Thirty-nine twin pairs performed spirometry of sufficient quality. Median gestational age at birth was 34.3 (interquartile range (IQR) 32.1-36.0) weeks with median birthweights of 1500 (IQR 1160-1880) grams and 2178 (IQR 1675-2720) grams for the smaller and larger twin, respectively. Smaller twins had significantly lower z-scores for FEV1 (-0.94 versus -0.41, p = 0.0015), FVC (-0.56 versus -0.06, p < 0.0001) and DLCO (-0.50 versus 0.00, p < 0.0001) compared to larger co-twins.
UNASSIGNED: Although being genetically identical, sFGR in identical twins is associated with a reduction in static and dynamic lung volume and a reduction in lung diffusion, even when taking the reduced lung volume into account. This indicates that adverse growth conditions in utero negatively affect lung development and function, potentially contributing to an increase in respiratory morbidities later in life.
UNASSIGNED: The Dutch Heart Foundation and The Bontius Foundation.

OBJECTIVE: To investigate the clinical outcomes and Doppler patterns changes in monochorionic diamniotic (MCDA) twins with selective fetal growth restriction (sFGR).
METHODS: We retrospectively analyzed 362 sFGR cases from January 2010 to May 2016 at a single tertiary referral center. The Doppler waveforms of umbilical artery end-diastolic flow were collected, and all neonates were subjected to an early neonatal brain scan.
RESULTS: A total of 66/100 (66 %) type I cases were stable, whereas 25/100 (25 %) cases changed to type II and 9/100 (9 %) changed to sFGR complicated twin-twin transfusion syndrome (TTTS). A total of 48.9 % (22/45) sFGR cases were complicated with polyhydramnios and 30.4 % (7/23) sFGR cases were complicated with oligohydramnios, both of which were progressed to sFGR with TTTS. Mild cerebral injury was significantly associated with Doppler flow abnormalities, earlier gestational age at delivery and type of sFGR diagnosis. Severe cerebral injury was significantly associated with gestational age at delivery (31.6 vs. 34.1, p=0.002) and larger birthweight discordance (43.9 vs. 29.3 %, p=0.011).
CONCLUSIONS: Doppler patterns in sFGR can gradually change, with important consequences with regard to management and outcomes. Along with abnormal Doppler findings, earlier occurrence of sFGR and delivery are associated with subsequent neonatal cerebral injury.

BACKGROUND: The aim of the study was to identify predictors of poor outcomes in monochorionic diamniotic twin (MCDA) pregnancies with selective fetal growth restriction (sFGR), irrespective of the umbilical artery (UA) Doppler abnormalities.
METHODS: Single-center retrospective analysis of MCDA twins diagnosed with sFGR that opted for expectant management between 2010 and 2021. The presence of any of the following variables in the growth-restricted fetus: low amniotic fluid volume (DVP ≤2 cm), lack of a cycling bladder, absent or reversed flow in the ductus venosus (DV) with atrial contraction, and elevated middle cerebral artery peak systolic velocity (MCA-PSV) defined as ≥1.50 multiples of the median was categorized as complicated. sFGR cases were classified as simple in the absence of the above-mentioned variables.
RESULTS: Overall, 63.3% of cases qualified as simple, and 36.7% were complicated. Intertwin EFW discordance was higher in the complicated category (26 vs. 33%, p = 0.0002). The median gestational age at delivery was earlier (33 weeks vs. 30.5 weeks, p = 0.002), and the likelihood of survival was lower in the complicated category (p < 0.0001). The likelihood of two survivors to discharge was lower in type I complicated cases (70% in complicated type I vs. 97.1% in simple type I, p = 0.0003). On logistic regression analysis, an increase in the \"complicated\" score negatively correlated with two survivors to discharge (p < 0.0001). An ROC curve was created, and the AUC was 0.79. Increasing intertwin EFW discordance also decreased the probability of two survivors to discharge.
CONCLUSIONS: The presence of oligohydramnios, lack of a cycling bladder, abnormal DV Doppler, and elevated MCA-PSV in the growth restricted fetus is associated with poor perinatal outcomes and a lower likelihood of having two survivors to discharge. The addition of intertwin EFW discordance to these variables helped improve the survival predictability.

This study investigated the impact of the shared intertwin circulation in unequally divided monochorionic (MC) placentas on fetal growth.
This retrospective analysis included color-dyed, unequally shared placentas from two tertiary centers. Exclusions included twin-twin transfusion syndrome, twin anemia polycythemia sequence, and lethal anomalies. Measurement of the external diameters and areas of the artery-to-artery (AA), artery-to-vein (AV), and vein-to-vein (VV) anastomoses was performed. The ratio of the shared circulation (AV ratio) was determined by comparing the areas of the summed venous components of shared AV anastomoses to those in the individual AV anastomoses of the smaller placental part. The birth weight ratio/placental ratio (BWR/PR), total AV size areas and net AV transfusion were calculated. Univariable and multivariable linear regressions were performed to assess the relationship between BWR/PR, the AV ratio, the areas of the different anastomoses and cord insertion discordance.
Among 352 placentas, 97 % (340) had intertwin AV anastomoses, and 50 % (176) were from pregnancies with selective growth restriction. The AV ratio, AA, VV, total AV areas, and cord insertion discordance negatively correlated with BWR/PR. Multivariable linear regression confirmed the independent negative association between BWR/PR and the AV ratio, suggesting that a larger shared circulation benefits the twin with the smaller placental part. Type III sFGR placentas exhibited the highest AV ratio, resulting in the lowest BWR/PR.
A larger shared circulation mitigates the impact of an unequally divided placenta on fetal growth. This effect surpasses the influence of AA and VV diameters and is most prominent in Type III sFGR placentas.

The distinct placental angioarchitecture in monochorionic (MC) pregnancies increases the risk of complications such as twin-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS), and selective fetal growth restriction (sFGR). The aim of this systematic review was to evaluate the incidence, type, and severity of cerebral injury and structural brain development on fetal and/or neonatal cerebral magnetic resonance imaging (MRI) in MC twins with or without complications. Twenty-three studies were included, covering a wide range of complications observed during MC pregnancies, with studies involving sIUFD (n = 12), TTTS (n = 7), mixed complications (n = 2), TAPS (n = 1), and uncomplicated MC pregnancy (n = 1). TAPS and sFGR were largely underrepresented in the current literature. The included studies reported that MC pregnancies with single intrauterine fetal demise (sIUFD) are most at risk for cerebral injury during the fetal period. The overall median incidence of cerebral injury after sIUFD was 28.3% (0-55%). Severe antenatal cerebral injury after sIUFD was detected antenatally in 6.5% (0-36%) of the cases. Three of the included studies described the incidence, type, and severity of cerebral injury on neonatal MRI in MC twins. Structural brain development based on cerebral biometry was only assessed in two studies, revealing significantly smaller biometric measurements of the cerebrum in cases of single sIUFD or smaller twins compared to singleton pregnancies. To enhance our understanding of the potential risks and pathophysiological mechanisms associated with cerebral injury and structural brain development in MC twins, there is a need for future studies and standardized protocols using serial fetal and neonatal MRI imaging in addition to routine ultrasound imaging.