Enhancing the Retinopathy Of Prematurity Risk Profile Through Placental Evaluation of Maternal and Fetal Vascular Malperfusion.

Purpose: To determine the independent effect of uteroplacental malperfusion on the development of retinopathy of prematurity (ROP). Methods: This cohort study included 591 neonates with a gestational age (GA) ≤ 32 weeks or birthweight (BW) ≤ 1500 g. Clinical data was retrospectively collected and placentas were prospectively examined for maternal vascular malperfusion (e.g., abruption, infarct, distal villous hypoplasia, ischemia, and decidual necrosis) and fetal vascular malperfusion (e.g., thrombosis, fetal hypoxia, and hydrops parenchyma). The primary outcome was ROP. Secondary outcomes were GA, BW, small for gestational age (SGA), mechanical ventilation duration, postnatal corticosteroids, sepsis, and necrotizing enterocolitis. Results: Maternal vascular malperfusion was associated with higher GA, lower BW, and increased SGA rates, except placental abruption, which was associated with lower SGA rates. Fetal vascular malperfusion was associated with lower BW, increased SGA rates and lower duration of mechanical ventilation. Subgroup analysis of placentas without inflammation showed increased rates of distal villous hypoplasia (44% vs. 31%) and hydrops parenchyma (7% vs. 0%) in neonates with ROP. Multivariate regression analyses revealed three placenta factors to be independently associated with ROP: distal villous hypoplasia (OR = 1.7; 95% CI, 1.0-3.0), severe acute histological chorioamnionitis (OR = 2.1; 95% CI, 1.1-3.9) and funisitis (OR = 1.8; 95% CI, 1.0-3.1). Conclusions: Placental evaluation of distal villous hypoplasia, severe acute chorioamnionitis and funisitis is a novel and valuable addition to the ROP risk profile. Evaluation of these placental risk factors shortly after birth can aid in identifying high-risk infants in an earlier stage than currently possible.

[Group A-streptococcal infection during pregnancy]. / Groep A-streptokokkeninfectie tijdens de zwangerschap.

Group A-streptococcal (GAS) infection can lead to various clinical presentations and is fulminant when it reaches the deep tissues, leading to a high morbidity and mortality. The severity of postpartum GAS infections is widely known. In this case report we describe the course of disease in a pregnant patient with GAS toxic shock syndrome with initial complaints of abdominal pain, diarrhea and fetal demise at first presentation. Within 10 hours this patient died. It is important to stay vigilant for a fulminant GAS infection in pregnant patients, to recognize it quickly and treat it adequately.

Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort.

OBJECTIVE (S): Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature. METHODS: In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm3. The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories. RESULTS: Serum PlGF was positively associated with uPVV and uPVS development (uPVV: ß = 0.39, 95% CI = 0.15;0.64; bifurcation points: ß = 4.64, 95% CI = 0.04;9.25; crossing points: ß = 4.01, 95% CI = 0.65;7.37; total vascular length: ß = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development. CONCLUSION(S): Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854.

Early-Onset Sepsis as an Early Predictor for Retinopathy of Prematurity: A Meta-analysis.

OBJECTIVE: Neonatal sepsis has been established as a risk factor for retinopathy of prematurity (ROP) but previous meta-analyses have predominately focused on late-onset sepsis (LOS). This meta-analysis aims to explore the association between early-onset sepsis (EOS) and the risk of ROP. STUDY DESIGN: Observational studies reporting (unadjusted) data on proven EOS in neonates with ROP were included. PubMed, Embase, and Cochrane Library were searched. Proven EOS was defined as a positive blood or cerebrospinal fluid culture. Effect sizes were calculated by using logistic random-effects models and meta-regression analyses. Primary outcomes were any stage ROP and severe ROP (≥stage 3, type I, aggressive [posterior] ROP, plus disease or requiring treatment). Potential confounders explored were gestational age at birth, birth weight, small for gestational age, maternal steroid use, necrotizing enterocolitis, LOS, and mechanical ventilation duration. RESULTS: Seventeen studies reporting the incidence of proven EOS in neonates with ROP were included. Proven EOS showed no significant association with any stage ROP (odds ratio [OR] = 1.90; 95% confidence interval [CI]: 0.96-3.79, p = 0.067) but heterogeneity between studies was significantly high. Neonates with proven EOS had an increased risk for severe ROP (OR = 2.21; 95% CI: 1.68-2.90), and no significant confounders influencing this effect size were found in the meta-regression analysis. CONCLUSION: Neonates with proven EOS are at increased risk of severe ROP. Neonatologists need to be aware that EOS is an early predictor of ROP and should adapt their policy and treatment decisions where possible to reduce ROP. KEY POINTS: · This meta-analysis reveals a 2.2-fold increased risk of severe ROP in neonates with proven EOS.. · Future studies should distinguish between EOS and LOS when investigating risk factors of ROP.. · Treatment decisions should be adapted where possible in neonates with EOS before ROP screening begins..

Placenta histology related to flow and oxygenation in fetal congenital heart disease.

BACKGROUND: Fetuses with congenital heart defects (CHD) show delayed neurodevelopment, fetal growth restriction (FGR) and placenta related complications. The neurodevelopmental delay may be, partly, attributed to placental factors. AIM: As both placental development and fetal aortic flow/oxygenation influence neurodevelopment, placentas were compared within fetal CHD groups based on aortic oxygenation and flow, aiming to unravel the true effects in the developmental processes. STUDY DESIGN: Placental tissues of pregnancies with fetal CHD and healthy controls were selected from biobanks of two Dutch academic hospitals (LUMC, UMCU). Additionally, biometry and Dopplers were assessed. SUBJECTS: CHD cases with reduced oxygenation (RO) towards the fetal brain were compared to cases with reduced flow (RF) in the aortic arch and healthy controls. Genetic abnormalities, termination of pregnancy, fetal demise and/or multiple pregnancies were excluded. OUTCOME MEASURES: Histological outcomes were related to fetal Dopplers and biometry. A placenta severity score was used to assess the severity of placental abnormalities per case. RESULTS: In CHD, significantly more delayed maturation, maternal vascular malperfusion, fetal hypoxia and higher placenta severity scores (median 14 in RO, 14 in RF, 5 in controls, p < 0.001) were observed. Doppler abnormalities (PI UA > p90, PI MCA < p10, CPR < p10) and FGR were more often found in CHD. There were no differences in placental abnormalities, fetal growth and fetal Dopplers between cases with RO and RF. CONCLUSION: Fetal hemodynamics in the ascending aorta could not be related to placenta characteristics. We hypothesize that placental development influences neurodevelopment in excess of hemodynamics in CHD cases.

Twisting the theory on the origin of human umbilical cord coiling featuring monozygotic twins.

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 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.

Histological analysis of (antral) follicle density in ovarian cortex tissue attached to stripped endometriomas.

PURPOSE: When resecting endometriomas with the stripping technique, in the majority of cases, a thin line of adjacent ovarian cortex is attached to the endometrioma. In this study, we performed histological analysis to determine (antral) follicle density in the ovarian cortex tissue attached to stripped endometriomas and assessed patient- and surgical characteristics that could affect this. METHODS: Histological slides of previously removed endometriomas were assessed. Follicles in the attached ovarian tissue were classified according to maturation, and follicular density was determined. Immunofluorescent staining of antral follicles in a subset of endometriomas was also performed. RESULTS: In 90 out of 96 included endometriomas (93.7%), ovarian tissue attached to the cyst wall was observed. One thousand nine hundred forty-four follicles at different maturation stages were identified (3 follicles/mm3). Follicle density was negatively associated with age (p < 0.001). Antral follicles (< 7-mm diameter) were present in the ovarian tissue attached to 35 endometriomas (36.5%) derived from younger patients compared to endometriomas where none were detected (30 versus 35 years, p = 0.003). Antral follicle density was 1 follicle/mm3. Based on immunofluorescence, healthy antral follicles were identified in two out of four examined endometriomas. CONCLUSIONS: Ovarian tissue attached to stripped endometriomas holds potential as a non-invasive source for antral follicles. In theory, application of IVM could be an interesting alternative FP option in young patients with endometriomas who undergo cystectomy in order to transform the surgical collateral damage to a potential oocyte source. Our results encourage future research with fresh tissue to further assess the quality and potential of these follicles. TRIAL REGISTRATION: Clinical Trials.gov Identifier: B21.055 (METC LDD), date of registration 12-08-2021, retrospectively registered.

Placental Pathology Contributes to Impaired Volumetric Brain Development in Neonates With Congenital Heart Disease.

BACKGROUND: Neonates with congenital heart disease are at risk for impaired brain development in utero, predisposing children to postnatal brain injury and adverse long-term neurodevelopmental outcomes. Given the vital role of the placenta in fetal growth, we assessed the incidence of placental pathology in fetal congenital heart disease and explored its association with total and regional brain volumes, gyrification, and brain injury after birth. METHODS AND RESULTS: Placentas from 96 term singleton pregnancies with severe fetal congenital heart disease were prospectively analyzed for macroscopic and microscopic pathology. We applied a placental pathology severity score to relate placental abnormalities to neurological outcome. Postnatal, presurgical magnetic resonance imaging was used to analyze brain volumes, gyrification, and brain injuries. Placental analyses revealed the following abnormalities: maternal vascular malperfusion lesions in 46%, nucleated red blood cells in 37%, chronic inflammatory lesions in 35%, delayed maturation in 30%, and placental weight below the 10th percentile in 28%. Severity of placental pathology was negatively correlated with cortical gray matter, deep gray matter, brainstem, cerebellar, and total brain volumes (r=-0.25 to -0.31, all P<0.05). When correcting for postmenstrual age at magnetic resonance imaging in linear regression, this association remained significant for cortical gray matter, cerebellar, and total brain volume (adjusted R2=0.25-0.47, all P<0.05). CONCLUSIONS: Placental pathology occurs frequently in neonates with severe congenital heart disease and may contribute to impaired brain development, indicated by the association between placental pathology severity and reductions in postnatal cortical, cerebellar, and total brain volumes.

First-trimester 3D power Doppler imaging markers of utero-placental vascular development are associated with placental weight and diameter at birth: The Rotterdam Periconception Cohort.

INTRODUCTION: Early utero-placental vascular development impacts placental development and function throughout pregnancy. We investigated whether impaired first-trimester utero-placental vascular development is associated with pathologic features of the postpartum placenta. METHODS: In this prospective observational study of 65 ongoing pregnancies, we obtained three-dimensional power Doppler ultrasounds of the placenta at 7, 9 and 11 weeks of gestation. We applied VOCAL software to measure placental volume (PV), virtual reality based segmentation to measure utero-placental vascular volume (uPVV) and applied a skeletonization algorithm to generate the utero-placental vascular skeleton (uPVS). Vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-, crossing- or vessel point). Following delivery, placentas were measured and histologically examined according to the Amsterdam criteria to assess maternal vascular malperfusion (MVM). We used linear mixed models to estimate trajectories of PV, uPVV and uPVS development. Multivariable linear regression analysis with adjustments for confounders was used to evaluate associations between PV, uPVV and uPVS development and features of the postpartum placenta. RESULTS: We observed no associations between first-trimester PV development and measurements of the postpartum placenta. Increased first-trimester utero-placental vascular development, reflected by uPVV (ß = 0.25 [0.01; 0.48]), uPVS end points (ß = 0.25 [0.01; 0.48]), bifurcation points (ß = 0.22 [0.05; 0.37]), crossing points (ß = 0.29 [0.07; 0.52]) and vessel points (ß = 0.09 [0.02; 0.17]) was positively associated with the postpartum placental diameter. uPVV was positively associated with postpartum placental weight. No associations were found with MVM. DISCUSSION: Development of the first-trimester utero-placental vasculature is associated with postpartum placental size, whereas placental tissue development contributes to a lesser extent.

Characterization of the human fetal gonad and reproductive tract by single-cell transcriptomics.

During human fetal development, sex differentiation occurs not only in the gonads but also in the adjacent developing reproductive tract. However, while the cellular composition of male and female human fetal gonads is well described, that of the adjacent developing reproductive tract remains poorly characterized. Here, we performed single-cell transcriptomics on male and female human fetal gonads together with the adjacent developing reproductive tract from first and second trimesters, highlighting the morphological and molecular changes during sex differentiation. We validated different cell populations of the developing reproductive tract and gonads and compared the molecular signatures between the first and second trimesters, as well as between sexes, to identify conserved and sex-specific features. Together, our study provides insights into human fetal sex-specific gonadogenesis and development of the reproductive tract beyond the gonads.

First Reported Histologically and Molecularly Confirmed Bilateral High-Grade Serous Ovarian Adenocarcinoma Metastasized to Placental Decidua of the Membranes.

A 43-year-old female presented with blood loss and persistent abdominal pain at 14 weeks of gestation. Ultrasound examination and subsequent magnetic resonance imaging (MRI) revealed bilateral multicystic uterine adnexa. Exploratory laparotomy was performed at 17 weeks of gestation and bilateral serous ovarian adenocarcinoma FIGO stage IIIC was diagnosed. Complete cytoreductive surgery (CRS) was not feasible at that moment. Nine days after the exploratory laparotomy, immature rupture of membranes and contractions occurred and she delivered a premature boy after 19 weeks of gestation. Pathological examination of the placenta revealed that her ovarian cancer metastasized to the membranes. We describe the first case of ovarian cancer metastasized to the decidua of the placental membranes with histological, immunohistochemical, and molecular confirmation. This case highlights the importance of conscientious evaluation of placenta and membranes in pregnant women with ovarian cancer.

Classification of Atretic Small Antral Follicles in the Human Ovary.

The reproductive lifespan in humans is regulated by a delicate cyclical balance between follicular recruitment and atresia in the ovary. The majority of the small antral follicles present in the ovary are progressively lost through atresia without reaching dominance, but this process remains largely underexplored. In our study, we investigated the characteristics of atretic small antral follicles and proposed a classification system based on molecular changes observed in granulosa cells, theca cells, and extracellular matrix deposition. Our findings revealed that atresia spreads in the follicle with wave-like dynamics, initiating away from the cumulus granulosa cells. We also observed an enrichment of CD68+ macrophages in the antrum during the progression of follicular atresia. This work not only provides criteria for classifying three stages of follicular atresia in small antral follicles in the human ovary but also serves as a foundation for understanding follicular degeneration and ultimately preventing or treating premature ovarian failure. Understanding follicular remodeling in the ovary could provide a means to increase the number of usable follicles and delay the depletion of the follicular reserve, increasing the reproductive lifespan.

Histological Chorioamnionitis and Funisitis as New Risk Factors for Retinopathy of Prematurity: A Meta-analysis.

OBJECTIVE: The role of placental inflammation in neonatal morbidities is underestimated due to lack of placental examination. This meta-analysis aims to assess the association between histological chorioamnionitis (HCA) with and without funisitis (FUN) and risk of retinopathy of prematurity (ROP). STUDY DESIGN: Forty-five studies reporting (unadjusted) data on HCA without FUN and HCA with FUN in neonates with ROP were included. Primary outcomes were any stage ROP and severe ROP. Potential confounders explored were gestational age (GA) at birth, birthweight, maternal steroid use, necrotizing enterocolitis, sepsis (suspected/proven) and mechanical ventilation duration. RESULTS: Neonates with HCA had increased risk for any stage ROP (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.3-2.4) and severe ROP (OR 1.5; 95% CI 1.2-1.8) compared with neonates without HCA. The rates of any stage ROP (OR 1.8; 95% CI 1.4-2.2) and severe ROP (OR 1.4; 95% CI 1.1-1.6) were higher in neonates with FUN compared with neonates without FUN. Multivariate meta-regression analysis suggests that lower GA increases the effect size between FUN and severe ROP. CONCLUSION: This meta-analysis confirms that presence of HCA and FUN are risk factors for any stage ROP and severe ROP. Structured histological placental examination of HCA and FUN may be a tool to further refine the ROP risk profile. KEY POINTS: · This systematic review confirms that HCA is a risk factor for ROP.. · This meta-analysis reveals that FUN results in an even higher risk for developing ROP.. · Placental examination of HCA/FUN may be a tool to further refine the ROP risk profile..

Inflammatory placental lesions are specifically observed in healthy oocyte donation pregnancies with extreme fetal-maternal incompatibility.

INTRODUCTION: Oocyte donation (OD) pregnancy is a risk factor for pre-eclampsia (PE). Due to a higher extent of fetal-maternal human leukocyte antigens (HLA) mismatching in OD pregnancies compared to naturally conceived (NC) and in vitro fertilization (IVF) pregnancies, the immune response in OD placentas is probably divergent and affects clinical outcomes. We hypothesized that placental pathology varies among diverse pregnancy conditions and is related to fetal-maternal HLA incompatibility. METHODS: Placental lesions were scored in four patient groups: OD-PE (n = 16), OD-healthy (n = 37), NC-PE (n = 45), and IVF-healthy (n = 17). All combinations were genotyped for HLA-A, -B, -C, -DR, and -DQ to calculate fetal-maternal HLA mismatches. Placentas showing chronic deciduitis with plasma cells were immunofluorescently stained with CD138 and the anti-inflammatory cytokine interleukin-10 (IL-10). RESULTS: The distribution and severity of placental lesions varied among groups. The OD-healthy group had the highest inflammation score and greatest extent of chronic deciduitis with plasma cells (p < 0.05). However, the majority of CD138+ plasma cells (90%) in OD-healthy group expressed IL-10, in contrast to the OD-PE group (58%). The OD-healthy group was separated into semi-allogeneic (≤5 HLA mismatches) and fully allogeneic (>5 mismatches) subgroups. The elevated inflammatory pathology score and chronic deciduitis with plasma cells were found more often in the HLA-class-I fully allogeneic OD-healthy group than the IVF-healthy group (p < 0.05). DISCUSSION: Placental inflammatory lesions are most often present in uncomplicated OD pregnancies. Immune cells that infiltrate these lesions might play an immunosuppressive role to protect OD pregnancies from complications when facing a higher extent of fetal-maternal HLA mismatching.

Cell-cell interactions during the formation of primordial follicles in humans.

Gametogenesis is a complex and sex-specific multistep process during which the gonadal somatic niche plays an essential regulatory role. One of the most crucial steps during human female gametogenesis is the formation of primordial follicles, the functional unit of the ovary that constitutes the pool of follicles available at birth during the entire reproductive life. However, the relation between human fetal germ cells (hFGCs) and gonadal somatic cells during the formation of the primordial follicles remains largely unexplored. We have discovered that hFGCs can form multinucleated syncytia, some connected via interconnecting intercellular bridges, and that not all nuclei in hFGC-syncytia were synchronous regarding meiotic stage. As hFGCs progressed in development, pre-granulosa cells formed protrusions that seemed to progressively constrict individual hFGCs, perhaps contributing to separate them from the multinucleated syncytia. Our findings highlighted the cell-cell interaction and molecular dynamics between hFGCs and (pre)granulosa cells during the formation of primordial follicles in humans. Knowledge on how the pool of primordial follicle is formed is important to understand human infertility.

A robust and standardized method to isolate and expand mesenchymal stromal cells from human umbilical cord.

BACKGROUND AIMS: Human 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. METHODS: Using 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. RESULTS: We 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. CONCLUSIONS: We 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.

Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25-100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI. METHOD: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast. RESULTS: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39. DISCUSSION: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI.

Factors related to fetal demise in cases with congenital heart defects.

BACKGROUND: Congenital heart defects are the most common congenital 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 prenatally during the period January 2002 to January 2021 were selected from the regional prospective congenital heart disease registry, PRECOR. Multiple 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 analysis 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 pregnancies, 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 ultrasonographic assessment of fetal growth and placental function in fetal congenital heart disease.