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.

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.

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..

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.

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.

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..

Increased Risk of Retinopathy of Prematurity in Donors with Twin-to-Twin Transfusion Syndrome: A Cohort Study.

INTRODUCTION: The purpose of this study was to evaluate the within-pair difference in retinopathy of prematurity (ROP) between donors and recipients with twin-to-twin transfusion syndrome (TTTS) and to identify risk factors for ROP development. METHODS: This retrospective cohort study included 147 TTTS twin pairs managed between 2002 and 2022 and eligible for ROP screening. Primary outcomes were any stage ROP and severe ROP. Secondary outcomes were hemoglobin at birth, red blood cell transfusions, mechanical ventilation days, postnatal steroids, and neonatal morbidity. Donor status was defined as having polyhydramnios pre-laser. RESULTS: Rates of any stage ROP (23% vs. 14%) and severe ROP (8% vs. 3%) were significantly higher in donors compared to recipients. Donors received a higher number of blood transfusions (1 [±1.9] versus 0.7 [±1.5]). Five factors were univariately associated with any stage ROP: donor status (odds ratio [OR] 1.9; 95% CI 1.3-2.9), lower gestational age (GA) at birth (OR 1.7; 95% CI 1.4-2.1), small for GA (OR 2.1; 95% CI 1.3-3.5), mechanical ventilation days (OR 1.1; 95% CI 1.1-1.2), and blood transfusions in phase 1 (OR 2.3; 95% CI 1.2-4.3). Three factors were independently associated with any stage ROP: donor status (OR 1.8; 95% CI 1.1-2.9), lower GA at birth (OR 1.6; 95% CI 1.2-2.1), and mechanical ventilation days (OR 1.1, 95% CI 1.0-1.1). Donor status was univariately associated with severe ROP (OR 2.3, 95% CI 1.1-5.0). CONCLUSION: Any stage ROP and severe ROP are detected twice as frequently in donors compared to recipients. Increased awareness for ROP is needed in donors, especially those with lower GA at birth and longer duration of mechanical ventilation.

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.

Impact of placental sharing and large bidirectional anastomoses on birthweight discordance in monochorionic twins: a retrospective cohort study in 449 cases.

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 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 share×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 (ß coefficient, 0.325; 95% confidence interval, 0.254-0.397; P<.0001). The arterioarterial diameter was negatively correlated with birthweight ratio/placental territory ratio (ß 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 (ß 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.

Subamniotic Hemorrhage, a Possible New Presentation of Fetal and Neonatal Alloimmune Thrombocytopenia.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare fetal disease in which maternal antibodies directed toward fetal human platelet antigens (HPA) are formed during pregnancy and cause fetal thrombocytopenia. The diagnosis FNAIT is suspected when a fetus or neonate presents with signs of bleeding. CASE: We describe a pregnancy complicated by a placental hematoma in the 20th week of gestation as the first manifestation of FNAIT. Further evaluation showed signs of germinal matrix hemorrhage and HPA-5b allo-antibodies. After the diagnosis, intravenous immunoglobulin was administered weekly and a healthy daughter was born at 37 weeks. Histopathological analysis revealed that the hematoma was caused by a subamniotic hemorrhage of fetal origin. CONCLUSION: A subamniotic hematoma appears to be the first manifestation of FNAIT.

Large Hemoglobin Differences at Birth in Monochorionic Twins with a Placental Chorangioma and Delayed Cord Clamping.

We report a case of a monochorionic diamniotic twin with an uncomplicated pregnancy, but with an unexpected large intertwin hemoglobin (Hb) difference at birth. Twin 1 was delivered vaginally and had an uneventful neonatal course. The umbilical cord of Twin 1 was clamped approximately 5 min after birth. After the birth of Twin 1, Twin 2 developed severe bradycardia and showed limited cardiac output on ultrasound, for which an emergency cesarean section was performed. A full blood count revealed an Hb of 20.1 g/dL for Twin 1 and 10.2 g/dL for Twin 2 (intertwin difference 9.9 g/dL). Reticulocyte counts were similar, 40‰ and 38‰, respectively. Placental examination revealed 10 vascular anastomoses, including one arterio-arterial anastomosis with a diameter of 1.4 mm. Additionally, a large chorangioma was present on the placental surface of Twin 2. There was no color difference on the maternal side of the placenta. Based on the reticulocyte count ratio and the placental characteristics, twin anemia polycythemia sequence was ruled out as the cause of the large intertwin Hb difference. In this report, we discuss the various potential causes that could explain the large intertwin Hb difference including the role of delayed cord clamping in Twin 1, and the role of a large chorangioma, which may have attracted blood from the fetal circulation of Twin 2.

One-Sided Chronic Intervillositis of Unknown Etiology in Dizygotic Twins: A Description of 3 Cases.

Chronic intervillositis of unknown etiology (CIUE) is a rare, poorly understood, histopathological diagnosis of the placenta that is frequently accompanied by adverse pregnancy outcomes including miscarriage, fetal growth restriction, and intrauterine fetal death. CIUE is thought to have an immunologically driven pathophysiology and may be related to human leukocyte antigen mismatches between the mother and the fetus. Dizygotic twins with one-sided CIUE provide an interesting context to study the influence of immunogenetic differences in such cases. The main immune-cell subsets were investigated using immunohistochemistry. We identified three dizygotic twin pregnancies in which CIUE was present in only one of the two placentas. Two of the pregnancies ended in term delivery and one ended in preterm delivery. Presence of CIUE was correlated with lower placental weight and lower birthweight. Relative number of CD68, CD56, CD20, and CD3 positive cells were comparable between co-twins. The presence of one-sided CIUE in dizygotic twin pregnancy was associated with selective growth restriction in the affected twin. This suggests a unique fetal immunogenetic contribution to the pathogenesis of CIUE. Further study of dizygotic and monozygotic placentas affected by CIUE could identify new insights into its pathophysiology and into the field of reproductive immunology.

Placental Complement Activation in Fetal and Neonatal Alloimmune Thrombocytopenia: An Observational Study.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.

[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.

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.

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.

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.

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.