The human umbilical cord (hUC) is the lifeline that connects the fetus to the mother. Hypercoiling of the hUC is associated with pre- and perinatal morbidity and mortality. We investigated the... Show moreThe human umbilical cord (hUC) is the lifeline that connects the fetus to the mother. Hypercoiling of the hUC is associated with pre- and perinatal morbidity and mortality. We investigated the origin of hUC hypercoiling using state-of-the-art imaging and omics approaches. Macroscopic inspection of the hUC revealed the helices to originate from the arteries rather than other components of the hUC. Digital reconstruction of the hUC arteries showed the dynamic alignment of two layers of muscle fibers in the tunica media aligning in opposing directions. We observed that genetically identical twins can be discordant for hUC coiling, excluding genetic, many environmental, and parental origins of hUC coiling. Comparing the transcriptomic and DNA methylation profile of the hUC arteries of four twin pairs with discordant cord coiling, we detected 28 differentially expressed genes, but no differentially methylated CpGs. These genes play a role in vascular development, cell–cell interaction, and axis formation and may account for the increased number of hUC helices. When combined, our results provide a novel framework to understand the origin of hUC helices in fetal development. Show less
Koning, M.A. de; Ramirez, P.A.P.; Haak, M.C.; Han, X.; Ruiterkamp-Versteeg, M.H.; Leeuw, N. de; ... ; Suerink, M. 2024
Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated... Show moreFetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops. Show less
Weeda, J.A.; Bokenkamp-Gramann, R.; Straver, B.B.; Rammeloo, L.; Hahurij, N.D.; Bertels, R.A.; ... ; Palen, R.L.F. van der 2023
BackgroundBalloon atrial septostomy (BAS) is an emergent and essential cardiac intervention to enhance intercirculatory mixing at atrial level in deoxygenated patients diagnosed with transposition... Show moreBackgroundBalloon atrial septostomy (BAS) is an emergent and essential cardiac intervention to enhance intercirculatory mixing at atrial level in deoxygenated patients diagnosed with transposition of the great arteries (TGA) and restrictive foramen ovale. The recent recall of several BAS catheters and the changes in the European legal framework for medical devices (MDR 2017/745), has led to an overall scarcity of BAS catheters and raised questions about the use, safety, and experience of the remaining NuMED Z-5 BAS catheter.AimsTo evaluate and describe the practice and safety of the Z-5 BAS catheter, and to compare it to the performance of other BAS catheters.MethodsA retrospective single-center cohort encompassing all BAS procedures performed with the Z-5 BAS catheter in TGA patients between 1999 and 2022.ResultsA total of 182 BAS procedures were performed in 179 TGA-newborns at Day 1 (IQR 0–5) days after birth, with median weight of 3.4 (IQR 1.2–5.7) kg. The need for BAS was urgent in 90% of patients. The percentage of BAS procedures performed at bedside increased over time from 9.8% (before 2010) to 67% (2017–2022). Major complication rate was 2.2%, consisting of cerebral infarction (1.6%) and hypovolemic shock (0.5%). The rate of minor complications was 9.3%, including temporary periprocedural AV-block (3.8%), femoral vein thrombosis (2.7%), transient intracardiac thrombus (0.5%), and atrial flutter (2.2%). BAS procedures performed at bedside and in the cardiac catheterization laboratory had similar complication rates.ConclusionsBAS using the Z-5 BAS catheter is both feasible and safe at bedside and at the cardiac catheterization laboratory with minimal major complications. Show less
Heurn, L.J. van; Coumans, A.; Haak, M.C.; Kaaij, A. van der; Heurn, L.W.E. van; Pajkrt, E.; Derikx, J.P.M. 2023
Several factors associated with poor outcome in patients with prenatally diagnosed sacrococcygeal teratoma (SCT) have been found. However, the prognostic accuracy of these factors has not been well... Show moreSeveral factors associated with poor outcome in patients with prenatally diagnosed sacrococcygeal teratoma (SCT) have been found. However, the prognostic accuracy of these factors has not been well established. Therefore, we aimed to systematically review the prognostic accuracy of factors associated with poor outcome in these patients. We queried Search Premier, COCHRANE Library, EMCARE, EMBASE, PubMed, ScienceDirect, and Web of Science databases to identify studies regarding patients with prenatally diagnosed SCT. Poor outcome was defined as termination of pregnancy (TOP), intrauterine fetal death (IUFD), or perinatal death. We estimated the odds ratio of factors associated with poor outcome. Eleven studies (447 patients) were included. Overall mortality, including TOP, was 34.9%. Factors associated with poor outcome in fetuses with prenatally diagnosed SCT were cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, and placentomegaly. A tumor volume to fetal weight ratio (TFR) of >0.12 before a gestational age of 24 weeks is predictive of poor outcome. The prognostic accuracy of factors associated with poor outcome in fetuses prenatally diagnosed with SCT seems promising. Factors associated with cardiac failure such as cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, placentomegaly, and TFR >0.12 were found to be predictive of poor outcome. Show less
Todtenhaupt, P.; Franken, L.A.; Groene, S.G.; Hoolwerff, M. van; Meeren, L.E. van der; Klink, J.M.M. van; ... ; Pel, M. van 2023
Background aimsHuman umbilical cord–derived mesenchymal stromal cells (hUC-MSCs) are increasingly used in research and therapy. To obtain hUC-MSCs, a diversity of isolation and expansion methods... Show moreBackground aimsHuman umbilical cord–derived mesenchymal stromal cells (hUC-MSCs) are increasingly used in research and therapy. To obtain hUC-MSCs, a diversity of isolation and expansion methods are applied. Here, we report on a robust and standardized method for hUC-MSC isolation and expansion.MethodsUsing 90 hUC donors, we compared and optimized critical variables during each phase of the multi-step procedure involving UC collection, processing, MSC isolation, expansion and characterization. Furthermore, we assessed the effect of donor-to-donor variability regarding UC morphology and donor attributes on hUC-MSC characteristics.ResultsWe demonstrated robustness of our method across 90 UC donors at each step of the procedure. With our method, UCs can be collected up to 6 h after birth, and UC-processing can be initiated up to 48 h after collection without impacting on hUC-MSC characteristics. The removal of blood vessels before explant cultures improved hUC-MSC purity. Expansion in Minimum essential medium α supplemented with human platelet lysate increased reproducibility of the expansion rate and MSC characteristics as compared with Dulbecco's Modified Eagle's Medium supplemented with fetal bovine serum. The isolated hUC-MSCs showed a purity of ∼98.9%, a viability of >97% and a high proliferative capacity. Trilineage differentiation capacity of hUC-MSCs was reduced as compared with bone marrow-derived MSCs. Functional assays indicated that the hUC-MSCs were able to inhibit T-cell proliferation demonstrating their immune-modulatory capacity.ConclusionsWe present a robust and standardized method to isolate and expand hUC-MSCs, minimizing technical variability and thereby lay a foundation to advance reliability and comparability of results obtained from different donors and different studies. Show less
BackgroundSince 2007 all pregnant women in the Netherlands are offered the second-trimester anomaly scan (SAS) in a nationwide prenatal screening program. This study aims to assess the level of... Show moreBackgroundSince 2007 all pregnant women in the Netherlands are offered the second-trimester anomaly scan (SAS) in a nationwide prenatal screening program. This study aims to assess the level of informed choice of women opting for the SAS and to evaluate the presence of routinization 16 years after its implementation. It further explores decisional conflict and women’s decision making.MethodsThis prospective national survey study consisted of an online questionnaire which was completed after prenatal counseling and before undergoing the SAS. Informed choice was measured by the adapted multidimensional measure of informed choice (MMIC) and was defined in case women were classified as value-consistent, if their decision for the SAS was deliberated and made with sufficient knowledge.ResultsA total of 894/1167 (76.6%) women completed the questionnaire. Overall, 54.8% made an informed choice, 89.6% had good knowledge, 59.8% had deliberated their choice and 92.7% held a positive attitude towards the SAS. Women with low educational attainment (p=0.004) or respondents of non-Western descent (p=0.038) were less likely to make an informed choice. Decisional conflict was low, with a significantly lower decisional conflict score in women that made an informed choice (p<0.001). Most respondents (97.9%) did not perceive pressure to undergo the SAS.ConclusionsOur study showed a relatively low rate of informed choice for the SAS, due to absence of deliberation. Therefore, some routinization seem to be present in the Netherlands. However, most women had sufficient knowledge, did not perceive pressure and experienced low decisional conflict. Show less
Groene, S.G.; Gremmen, I.J.; Zwet, E.W. van; Roest, A.A.W.; Haak, M.C.; Klink, J.M.M. van; ... ; Bruin, C. de 2023
ObjectiveResearch suggests that postnatal catch-up growth after fetal growth restriction (FGR) occurs frequently. Yet, postnatal growth in singletons may be influenced by multiple factors.... Show moreObjectiveResearch suggests that postnatal catch-up growth after fetal growth restriction (FGR) occurs frequently. Yet, postnatal growth in singletons may be influenced by multiple factors. Identical twins with discordant prenatal growth, termed selective FGR (sFGR), can be regarded as a natural experiment eliminating these sources of bias.DesignObservational cohort study.MethodsMonochorionic twins with sFGR born between 2002 and 2017 (aged 3-17 years) were eligible. Growth measurements (height, weight, head circumference, and body mass index) were performed at follow-up. Detailed growth curves documented by a systematic primary care system in the Netherlands were collected. Measurements were converted to standard deviation scores (SDSs). A mixed-effects model was used to assess within-pair SDS difference and individual height SDS relative to target height SDS.ResultsForty-seven twin pairs (94 children) were included at a median age of 11 (interquartile range 8-13) years. At the last measurement, smaller twins at birth had a lower height SDS [−0.6 vs −0.3, P < .001, median difference 0.5 (95%CI 0.4-0.7)], lower weight SDS [−0.5 vs −0.1, P < .001, median difference 0.8 (95%CI 0.5-1.0)], and lower head circumference SDS [−0.5 vs 0.2, P < .001, median difference 0.8 (95%CI 0.6-0.9)] compared to larger twins. These differences persisted until the age of 17. Smaller twins showed rapid catch-up growth in the first 2 years and reached their target height range between 8 and 11 years.ConclusionsIdentical twins with discordant prenatal growth maintain a modest but significant difference in height, weight, and head circumference, indicating a persistent, inhibitory effect of an adverse intrauterine environment on childhood growth. Show less
ObjectivesFirst-trimester ultrasound screening is increasingly performed to detect fetal anomalies early in pregnancy, aiming to enhance reproductive autonomy for future parents. This study aims to... Show moreObjectivesFirst-trimester ultrasound screening is increasingly performed to detect fetal anomalies early in pregnancy, aiming to enhance reproductive autonomy for future parents. This study aims to display the current practice of first-trimester ultrasound screening in developed countries. MethodAn online survey among 47 prenatal screening experts in developed countries. ResultsFirst-trimester structural anomaly screening is available in 30 of the 33 countries and is mostly offered to all women with generally high uptakes. National protocols are available in 23/30 (76.7%) countries, but the extent of anatomy assessment varies. Monitoring of scan quality occurs in 43.3% of the countries. 23/43 (53.5%) of the respondents considered the quality of first-trimester ultrasound screening unequal in different regions of their country. ConclusionsFirst-trimester screening for structural fetal anomalies is widely offered in developed countries, but large differences are reported in availability and use of screening protocols, the extent of anatomy assessment, training and experience of sonographers and quality monitoring systems. Consequently, this results in an unequal offer to parents in developed countries, sometimes even within the same country. Furthermore, as offer and execution differ widely, this has to be taken into account when results of screening policies are scientifically published or compared. Show less
Lugthart, M.A.; Verbaarschot, E.; Nisselrooij, A.E.L. van; Kamp, K. van de; Kleinrouweler, E.; Haak, M.C.; ... ; Pajkrt, E. 2023
Introduction: Early detection of isolated severe congenital heart defects (CHDs) allows extra time for chromosomal analysis and informed decision making, resulting in improved perinatal management... Show moreIntroduction: Early detection of isolated severe congenital heart defects (CHDs) allows extra time for chromosomal analysis and informed decision making, resulting in improved perinatal management and patient satisfaction. Therefore, the aim of this study was to assess the value of an additional first-trimester screening scan compared to only a second-trimester scan in fetuses diagnosed with isolated severe CHDs. Prenatal detection rate, time of prenatal diagnosis, and pregnancy outcome were evaluated in the Netherlands after implementation of a national screening program.Materials and methods: We performed a retrospective geographical cohort study and included 264 pre- and postnatally diagnosed isolated severe CHD cases between January 1, 2007, and December 31, 2015, in the Amsterdam region. Severe CHD was defined as potentially life threatening if intervention within the first year of life was required. Two groups were defined: those with a first- and second-trimester anomaly scan (group 1) and those with a second-trimester anomaly scan only (group 2). A first-trimester scan was defined as a scan between 11 + 0 and 13 + 6 weeks of gestation.Results: Overall, the prenatal detection rate for isolated severe CHDs was 65%; 63% were detected before 24 weeks of gestation (97% of all prenatally detected CHDs). Prenatal detection rate was 70.2% in the group with a first- and second-trimester scan (group 1) and 58% in the group with a second-trimester scan only (group 2) (p < 0.05). Median gestational age at detection was 19 + 6 (interquartile range [IQR] 15 + 4 - 20 + 5) in group 1 versus 20 + 3 (IQR: 20 + 0 - 21 + 1) in group 2 (p < 0.001). In group 1, 22% were diagnosed before 18 weeks of gestation. Termination of pregnancy rate in group 1 and group 2 were 48% and 27%, respectively (p < 0.01). Median gestational age at termination did not differ between the two groups.Conclusion: Prenatal detection rate of isolated severe CHDs and termination of pregnancy rate was higher in the group with both a first- and second-trimester scan. We found no differences between timing of terminations. The additional time after diagnosis allows for additional genetic testing and optimal counseling of expectant parents regarding prognosis and perinatal management, so that well-informed decisions can be made. Show less
BACKGROUND: Congenital heart defects are the most common con-genital anomaly. Despite the increasing survival of these children, there is still an increased incidence of fetal demise, frequently... Show moreBACKGROUND: Congenital heart defects are the most common con-genital anomaly. Despite the increasing survival of these children, there is still an increased incidence of fetal demise, frequently attributed to cardiac failure. Considering that abnormal placental development has been described in congenital heart disease, our hypothesis is that placental insufficiency may contribute to fetal death in congenital heart disease.OBJECTIVE: This study aimed to assess cases with fetal congenital heart disease and intrauterine demise, and analyze factors that are related to the demise.STUDY DESIGN: All congenital heart disease cases diagnosed prena-tally during the period January 2002 to January 2021 were selected from the regional prospective congenital heart disease registry, PRECOR. Multi-ple pregnancies and pregnancies with fetal trisomy 13 or 18, triploidy, and Turner's syndrome were excluded from the analysis, because fetal demise is attributed to the chromosomal abnormality in these cases. Cases were categorized into 4 groups based on the possible cause of fetal death as follows: cardiac failure, additional (genetic) diagnosis, placental insufficiency, and a group in which no cause was found. A separate analy-sis was performed for isolated congenital heart disease cases.RESULTS: Of the 4806 cases in the PRECOR registry, 112 had fetal demise, of which 43 were excluded from the analysis (13 multiple preg-nancies, 30 genetic). Of these, 47.8% were most likely related to cardiac failure, 42.0% to another (genetic) diagnosis, and 10.1% to placental insufficiency. No cases were allocated to the group with an unknown cause. Only 47.8% of the cases had isolated congenital heart disease, and in this group 21.2% was most likely related to placental insufficiency.CONCLUSION: This study shows that in addition to cardiac failure and other (genetic) diagnoses, placental factors play an important role in fetal demise in congenital heart disease, especially in cases of isolated heart defects. Therefore, these findings support the importance of regular ultra-sonographic assessment of fetal growth and placental function in fetal congenital heart disease. Show less
Introduction: Perforation of the intertwin membrane can occur as a complication of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS). Data on the occurrence and the risk of... Show moreIntroduction: Perforation of the intertwin membrane can occur as a complication of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS). Data on the occurrence and the risk of subsequent cord entanglement is limited. The objective of this study is to assess the prevalence, risk factors and outcome of intertwin membrane perforation and cord entanglement after laser surgery for TTTS. Methods: In this multicenter retrospective study, we included all TTTS pregnancies treated with laser surgery in two fetal therapy centers, Shanghai (China) and Leiden (The Netherlands) between 2002 and 2020. We evaluated the occurrence of intertwin membrane perforation and cord entanglement after laser, based on routine fortnightly ultrasound examination and investigated the risk factors and the association with adverse short- and long-term outcome. Results: Perforation of the intertwin membrane occurred in 118 (16%) of the 761 TTTS pregnancies treated with laser surgery and was followed by cord entanglement in 21% (25/118). Perforation of the intertwin membrane was associated with higher laser power settings, 45.8 Watt versus 42.2 Watt (p=0.029) and a second fetal surgery procedure 17% versus 6% (p<0.001). The group with intertwin membrane perforation had a higher rate of caesarean section (77% versus 31%, p<0.001) and a lower gestational age at birth (30.7 versus 33.3 weeks of gestation, p<0.001) compared to the group with an intact intertwin membrane. Severe cerebral injury occurred more often in the group with intertwin membrane perforation, 9% (17/185) versus 5% (42/930) respectively (p=0.019). Neurodevelopmental outcome at two years of age was similar between the groups with and without perforation of the intertwin membrane and between the subgroups with and without cord entanglement. Conclusion: Perforation of the intertwin membrane after laser occurred in 16% of TTTS cases treated with laser and led to cord entanglement in at least one in five cases. Intertwin membrane perforation was associated with a lower gestational age at birth and a higher rate of severe cerebral injury in surviving neonates. Show less
Oratie uitgesproken door Prof.dr. M.C. Haak bij de aanvaarding van het ambt van hoogleraar met als leeropdracht Verloskunde, in het bijzonder Foetale Cardiologie aan de Universiteit Leiden op... Show moreOratie uitgesproken door Prof.dr. M.C. Haak bij de aanvaarding van het ambt van hoogleraar met als leeropdracht Verloskunde, in het bijzonder Foetale Cardiologie aan de Universiteit Leiden op vrijdag 2 juni 2023 Show less
ObjectiveTo assess the perinatal outcome after fetal reduction in complicated monochorionic (MC) twin pregnancies by comparing different techniques. MethodsA retrospective cohort study at a... Show moreObjectiveTo assess the perinatal outcome after fetal reduction in complicated monochorionic (MC) twin pregnancies by comparing different techniques. MethodsA retrospective cohort study at a national referral center comparing data between four techniques: interstitial laser coagulation, radiofrequency ablation (RFA), fetoscopic laser coagulation (FLC) and bipolar cord coagulation (BCC). The primary outcome was the mortality of the co-twins. Secondary outcomes were preterm pre-labor rupture of membranes (PPROM), gestational age at delivery and neonatal morbidity. Results259 MC twin pregnancies underwent selective fetal reduction: 29 IL, 64 RFA, 85 FLC and 81 BCC. The perinatal mortality rate was 29% and fetal demise of the co-twins occurred in 19%. The lowest mortality rate was seen after BCC (17%, p = 0.012). PPROM occurred in 18% patients without significant differences between techniques. The mean gestational age at delivery in liveborn children was 35 weeks and did not differ between techniques. Severe cerebral injury and neonatal morbidity were reported in 4% and 14%, respectively, without significant differences between techniques. ConclusionsSelective fetal reductions in MC twins are precarious procedures with an increased risk of perinatal mortality of the co-twins. Our results show the lowest mortality rates after BCC. However, high PPROM rates were seen irrespective of the technique. Show less
Aliasi, M.; Mastenbroek, M.; Papakosta, S.; Geloven, N. van; Haak, M.C. 2023
ObjectiveCongenital heart disease (CHD) is associated with decreased birthweight (BW) compared to population-based references. The aim of this study was to compare the BW of isolated CHD cases to... Show moreObjectiveCongenital heart disease (CHD) is associated with decreased birthweight (BW) compared to population-based references. The aim of this study was to compare the BW of isolated CHD cases to their siblings, thus controlling for unknown and unmeasured confounders within the family. MethodsAll isolated CHD cases in the Leiden University Medical Center were included (2002-2019). Generalized estimated equation models were constructed to compare BW z scores of CHD neonates with their siblings. Cases were clustered to minor or severe CHD and stratified according to the aortic flow and oxygenation to the brain. ResultsThe overall BW z score of siblings was 0.032 (n = 471). The BW z score was significantly lower in CHD cases (n = 291) compared to their siblings (-0.20, p = 0.005). The results were consistent in the subgroup analysis of severe and minor CHD (BW z score difference -0.20 and -0.10), but did not differ significantly (p = 0.63). Stratified analysis regarding flow and oxygenation showed no BW difference between the groups (p = 0.1). ConclusionIsolated CHD cases display a significantly lower BW z score compared to their siblings. As the siblings of these CHD cases show a BW distribution similar to the general population, this suggests that shared environmental and maternal influences between siblings do not explain the difference in BW. Show less
Bet, B.B.; Snoep, M.C.; Leeuwen, E. van; Linskens, I.H.; Haak, M.C.; Rozendaal, L.; ... ; Pajkrt, E. 2023
ObjectivesTo determine the proportion of children that require surgery in the first year of life and thereafter in order to improve the counseling of parents with a fetus with a right aortic arch ... Show moreObjectivesTo determine the proportion of children that require surgery in the first year of life and thereafter in order to improve the counseling of parents with a fetus with a right aortic arch (RAA). MethodsFetuses diagnosed with isolated RAA, defined as the absence of intra- or extracardiac anomalies, between 2007 and 2021 were extracted from the prospective registry PRECOR. ResultsIn total, 110 fetuses were included, 92 with a prenatal diagnosis of RAA and 18 with double aortic arch (DAA). The prevalence of 22q11 deletion syndrome was 5.5%. Six pregnancies were terminated and five cases were false-positive; therefore, the follow-up consisted of 99 neonates. Surgery was performed in 10 infants (10%) in the first year of life. In total, 25 (25%) children had surgery at a mean age of 17 months. Eight of these 25 (32%) had a DAA. Only one child, with a DAA, required surgery in the first week of life due to obstructive stridor. ConclusionsChildren with a prenatally diagnosed RAA are at a low risk of acute respiratory postnatal problems. Delivery in a hospital with neonatal intensive care and pediatric cardiothoracic facilities seems only indicated in cases with suspected DAA. Expectant parents should be informed that presently 25% of the children need elective surgery and only incidentally due to acute respiratory distress. Show less
Objective: We aimed to assess current prenatal detection rate (DR) of aortic coarctation (CoA) and its impact on neonatal outcome in the Netherlands to evaluate the efficacy of the Dutch screening... Show moreObjective: We aimed to assess current prenatal detection rate (DR) of aortic coarctation (CoA) and its impact on neonatal outcome in the Netherlands to evaluate the efficacy of the Dutch screening protocol in which the cardiac four-chamber view, outflow tracts and three-vessel view are compulsory. Methods: All prenatally and postnatally diagnosed CoA cases between 2012 and 2021 were extracted from our PRECOR-registry. Annual DRs were calculated with a focus on the trend over time and attributing factors for detection. Postnatal outcome was compared between prenatally detected and undetected cases. Results: 49/116 cases (42.2%) were detected prenatally. A higher chance of detection was found for cases with extracardiac malformations (71.4%; p = 0.001) and the more severe cases with an aortic arch hypoplasia and/or ventricular septal defect (63.2%; p = 0.001). Time-trend analysis showed no improvement in DR over time (p = 0.33). Undetected cases presented with acute circulatory shock in 20.9% and were more likely to have severe lactic acidosis (p = 0.02) and impaired cardiac function (p < 0.001) before surgery. Conclusion: Even in a well-organized screening program, the DR of CoA still requires improvement, especially in isolated cases. The increased risk of severe lactic acidosis in undetected cases stresses the need for urgent additions to the current screening program, such as implementation of the three-vessel trachea view and measurement of outflow tracts. Show less
BACKGROUND: In monochorionic twin pregnancies, the fetuses share a single placenta. When this placenta is unequally shared, a discordant antenatal growth pattern ensues resulting in high rates of... Show moreBACKGROUND: In monochorionic twin pregnancies, the fetuses share a single placenta. When this placenta is unequally shared, a discordant antenatal growth pattern ensues resulting in high rates of perinatal morbidity and mortality. Understanding placental pathophysiology is paramount in devising feasible antenatal management strategies. Unequal placental sharing is not the sole determinant of birthweight discordance as there is no one-to-one relationship with placental share discordance. Placental angioarchitecture, especially the presence of large bidirectional anastomoses, is thought to affect this relationship by allowing for a compensatory intertwin blood flow. OBJECTIVE: This study aimed to assess whether placental angioarchitecture can affect birthweight discordance in live-born monochorionic twins, the aim of our study was 2-fold: (1) to assess the relationship between birthweight discordance and placental share discordance and (2) to examine to what extent large bidirectional anastomoses can compensate for the effect of unequal placental sharing on birthweight discordance, with a subgroup analysis for umbilical artery Doppler flow patterns in cases with a birthweight discordance of >= 20%. STUDY DESIGN: This was a retrospective cohort study that included monochorionic twin pregnancies observed in our center between March 2002 and June 2021, in which twins with a birthweight discordance of >= 20% were classified according to umbilical artery Doppler flow patterns of the smaller twin. We excluded cases with twin-twin transfusion syndrome and twin anemia polycythemia sequence. Monochorionic placentas of live-born twins were injected with dye, and images were saved for computer measurements of placental sharing and the diameter of anastomoses. Univariate linear regressions of the relationship between placental share discordance and birthweight discordance (both calculated as larger weight or share- smaller weight or share/larger weight or sharex 100%) and the relationship between arterioarterial and venovenous diameters and birthweight ratio/placental territory ratio were performed. RESULTS: A total of 449 placentas were included in the analysis. Placental share discordance was positively correlated with birthweight discordance (b coefficient, 0.325; 95% confidence interval, 0.254-0.397; P<.0001). The arterioarterial diameter was negatively correlated with birthweight ratio/placental territory ratio (b coefficient, -0.041; 95% confidence interval, -0.059 to -0.023; P<.0001), meaning that an increase in arterioarterial diameter leads to less birthweight discordance than expected for the amount of placental share discordance. There was no relationship between venovenous diameter and birthweight ratio/placental territory ratio (b coefficient, -0.007; 95% confidence interval, -0.027 to 0.012; P=.473). CONCLUSION: Birthweight discordance in monochorionic twins was strongly associated with placental share discordance. Large arterioarterial anastomoses can mitigate the effect of unequal placental sharing. Show less
Background: Psychosocial development in monochorionic (MC) twins born after selective fetal growth restriction (sFGR) has been unreported to date, despite its importance for daily functioning and... Show moreBackground: Psychosocial development in monochorionic (MC) twins born after selective fetal growth restriction (sFGR) has been unreported to date, despite its importance for daily functioning and future relationships. Aims: To investigate psychosocial development, attachment and school functioning in MC twins with sFGR and compare outcomes with the general population and between smaller and larger twins. Study design: Observational cohort study. Subjects: MC twins with sFGR (defined as a birth weight discordance >= 20 %) born between 2002 and 2017 and aged 3-17 years. Outcome measures: Multiple parent report questionnaires: the Child Behavior Checklist (social-emotional devel-opment and behavior), the (Early) Childhood Behavior Questionnaire Very Short Form (temperament), the Attachment Insecurity Screening Inventory (attachment) and a school functioning questionnaire. Results: Median age for the 48 twin pairs was 11 (interquartile range (IQR) 8-13) years. Attachment insecurity for both twins was higher than in the general population for ambivalence/resistance (34 % (21/62) vs. 16 %, p = 0.024) and total attachment insecurity (35 % (22/62) vs. 16 %, p = 0.016). Smaller twins had more internalizing behavioral problems, i.e. negative emotions and behaviors turned inwards (22 % (10/46) vs. 11 % (5/46), p = 0.021) and a higher negative affect, i.e. more likely to experience negative emotions (3.2 (2.9-3.7) vs. 2.9 (2.2-3.2), p = 0.009) than larger twins, as well as a lower secondary school level (p = 0.031). Conclusion: MC twins with sFGR have more ambivalent/resistant attachment insecurity following the compli-cated pregnancy course. Smaller twins have a tendency towards negative emotions and internalizing behaviors compared to larger twins, indicating an increased sensitivity for depression and anxiety. Show less
Koopmann, T.T.; Jamshidi, Y.; Naghibi-Sistani, M.; Klift, H.M. van der; Birjandi, H.; Al-Hassnan, Z.; ... ; Maroofian, R. 2022
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in... Show moreAutosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism. Show less
Koopmann, T.T.; Jamshidi, Y.; Naghibi-Sistani, M.; Klift, H.M. van der; Birjandi, H.; Al-Hassnan, Z.; ... ; Maroofian, R. 2022
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in... Show moreAutosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism. Show less
