Maternal outcomes of a cohort of pregnancies affected by non-immune hydrops fetalis.

OBJECTIVE: To describe the maternal outcomes of a prospective cohort of non-immune hydrops fetalis (NIHF) pregnancies with negative standard-of-care evaluations. METHODS: This study was a secondary analysis of a prospective cohort study of NIHF pregnancies with negative work-ups (infection, alloimmune anemia, fetomaternal hemorrhage, and chromosomal disorders). Outcomes were obstetric complications, including pre-eclampsia, mirror syndrome, preterm birth, polyhydramnios, postpartum hemorrhage, and maternal mental health. RESULTS: Forty pregnancies were included. Four patients developed pre-eclampsia (4/40, 10.0%); three occurred postpartum. None was diagnosed with mirror syndrome. Of the 31 continued pregnancies, 16 (51.6%) resulted in early fetal death or stillbirth and 15 (48.4%) resulted in live births. Of the 15 live births, 8 (53.3%) were delivered by primary cesarean delivery; 5 (62.5%) were for hydrops fetalis. Eleven live births (73.3%) were delivered preterm; 9 (81.8%) were indicated, most commonly for fetal indications (7/9, 77.8%). Polyhydramnios occurred in 14/40 (35.0%) cases. Where EBL was recorded (n=37), there were 5 (13.5%) cases of postpartum hemorrhage and an additional 3 (8.1%) had uterine atony without hemorrhage. Eighteen patients (18/40, 45.0%) had new-onset or exacerbated depression or anxiety symptoms. CONCLUSION: Our study identified several important adverse outcomes of pregnancies complicated by NIHF with negative standard-of-care evaluations, including a high rate of postpartum pre-eclampsia and worsened mental health. We identified a higher rate of cesarean delivery and preterm birth, both primarily for fetal indications. We also observed the known relationship between polyhydramnios, hemorrhage, and atony, but noted that this risk included pregnancies concluding in dilation and evacuation. Counseling after a diagnosis of NIHF should include these adverse outcomes.

RASopathies are the most common set of monogenic syndromes identified by exome sequencing for nonimmune hydrops fetalis: A systematic review and meta-analysis.

RASopathies are a group of malformation syndromes known to lead to nonimmune hydrops fetalis (NIHF) in severe presentations. Pathogenic variants can be de novo or parentally inherited. Despite being a known frequent presentation, the fraction of monogenic NIHF cases due to RASopathies is limited in the literature. Also, the specific parental contribution of RASopathies to NIHF is not well described. Our objective was to review pooled exome sequencing (ES) diagnostic yield of RASopathies for NIHF and to determine the parental contribution of RASopathy to NIHF. We performed a systematic review of prenatal ES studies from January 1, 2000 to August 1, 2022. Thirty-six studies met inclusion criteria. Cases with RASopathy gene variants were reviewed. NIHF cases were further classified as isolated or non-isolated. Thirty-six ES studies including 46 pregnancies with NIHF and a diagnosed RASopathy were reviewed. Forty-four diagnostic variants and 2 variants of uncertain significance in 12 RASopathy genes were identified. Expanding on what was previously published, a total of 506 NIHF cases were extracted with 191 cases yielding a positive diagnosis by ES. The overall rate of RASopathy diagnosis in clinically diagnosed NIHF cases was 9% (44/506). The rate of RASopathy diagnosis among NIHF cases with positive genetic diagnosis by ES was 23% (44/191). Of the 46 cases identified, 13 (28%) variants were parentally inherited; specifically, 5/13 (38%) maternal, 3/13 (23%) paternal, 2/13 (15%) biparental, and 3/13 (23%) unspecified. Majority of NIHF cases 29/46 (63%) were isolated. Among NIHF cases with positive ES diagnoses, RASopathy diagnostic yield by ES was 23%. NIHF secondary to RASopathies was parentally inherited in 28% of cases. Most cases of NIHF due to RASopathy were isolated, with no prenatal detection of associated anomalies.

PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing.

OBJECTIVE: To clarify the relevance of PIEZO1 variants detected by prenatal exome in the context of non-immune hydrops fetalis (NIHF). METHODS: A systematic review of prenatal exome studies from 1/1/2000-8/1/2022 was performed. Thirty-six studies met the inclusion criteria. PIEZO1 variants were categorized by disease mode (dominant (AD) versus recessive (AR)) and classified by the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Twenty-two pregnancies with 35 distinct PIEZO1 variants were included. We deemed PIEZO1 variants to be "likely diagnostic" in 12/22 pregnancies, "possibly diagnostic" in 7/22, and "unlikely diagnostic" in 3/22. In total, 19 of 191 NIHF cases diagnosed by prenatal exome were attributed to PIEZO1. Among likely diagnosed cases, the disease mode was AR in eight and AD in four. PIEZO1 variants causing AR NIHF were characterized by loss of function and isolated NIHF phenotype. PIEZO1 variants causing AD NIHF were characterized by gain of function in red blood cells, scarcity in databases, and sporadic inheritance. Missense variants associated with NIHF were clustered in three domains: transmembrane helical unit 4 (THU4), THU5, and the Cap. CONCLUSION: PIEZO1 variants were reported in 10% of NIHF cases diagnosed by prenatal exome, making PIEZO1 the most common single gene reported in NIHF.

Imaging and outcomes of fetal adrenal hemorrhage: A systematic review.

OBJECTIVE: To describe prenatal and postnatal imaging findings of fetal adrenal hemorrhage (FAH) and its associated perinatal outcomes, including frequency of postnatal surgical intervention. METHOD: A systematic literature review of seven electronic databases was conducted from inception until January 2022, with 2008 articles identified reporting prenatally identified fetal adrenal masses. Studies with confirmed FAH diagnosis were included. Quality and risk assessment were evaluated. RESULTS: Thirty-five studies, including 102 FAH cases, were analyzed. FAH was commonly described as cystic (28/90, 31%), anechoic (25/90, 28%), or mixed echogenic (14/90, 16%) on ultrasound. Outcome data were available for 65 cases (64%) of FAH: 9% (6/65) resolved prenatally, 35% (23/65) resolved postnatally, 34% (22/65) regressed in size after birth, and 22% (14/65) persisted postnatally. Overall, 25% (16/65) of cases underwent postnatal surgical intervention. Neuroblastoma was suspected in all 16 surgical cases. Only one case (1/16, 6%) confirmed a cystic hematoma with microscopic islets of neuroblastoma in situ on pathology. CONCLUSION: Prenatal diagnosis of FAH is challenging due to the significant heterogeneity of ultrasound findings. Final pathology did not support the need for surgical intervention. Persistent postnatal FAH warrants shared decision making for further management based on the clinical presentation.

Diagnostic yield from prenatal exome sequencing for non-immune hydrops fetalis: A systematic review and meta-analysis.

Non-immune hydrops fetalis (NIHF) has multiple genetic etiologies diagnosable by exome sequencing (ES). We evaluated the yield of prenatal ES for NIHF, and the contribution of additional clinical findings and history. Systematic review was performed with PROSPERO tag 232951 using CINAHL, PubMed, and Ovid MEDLINE from January 1, 2000 through December 1, 2021. Selected studies performed ES to augment standard prenatal diagnostic approaches. Cases meeting a strict NIHF phenotype were tabulated with structured data imputed from papers or requested from authors. Genetic variants and diagnostic outcomes were harmonized across studies using current ACMG and ClinGen variant classification guidelines. Thirty-one studies reporting 445 NIHF cases had a 37% (95% CI: 32%-41%) diagnostic rate. There was no significant difference between isolated NIHF and NIHF with fetal malformations or between recurrent and simplex cases. Diagnostic rate was higher for consanguineous than non-consanguineous cases. Disease categories included RASopathies (24%), neuromuscular (21%), metabolic (17%), lymphatic (13%), other syndromes (9%), cardiovascular (5%), hematologic (2%), skeletal (2%), and other categories (7%). Inheritance patterns included recessive (55%), dominant (41%), and X-linked (4%). ES should be considered in the diagnostic workup of NIHF with and without associated ultrasound findings regardless of history of recurrence or consanguinity.

Prenatal phenotype of 47, XXY (Klinefelter syndrome).

OBJECTIVE: There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis is currently limited by a poor understanding of the prenatal phenotype of this condition. METHODS: This is a case series of fetuses with cytogenetically confirmed 47, XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four academic institutions between 2006 and 2019. Ultrasound reports were reviewed in detail to assess for increased nuchal translucency and structural abnormalities. Additionally, we reviewed results of cell-free DNA and serum analyte testing when performed to inform our understanding of the detection of fetal 47, XXY through standard genetic screening tests. RESULTS: Forty-one cases with confirmed cytogenetic diagnosis of 47, XXY and prenatal records available for review were identified: 37 had a prenatal diagnosis and 4 had a postnatal diagnosis. Nuchal translucency was increased ≥3.0 mm in 23.1% (6/26) of cases with a documented measurement. In 29.2% (7/24) of cases with a second trimester anatomical ultrasound available for review, a fetal abnormality was identified (3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities). Among those who had cell-free DNA and serum analytes performed, 92.6% (25/27) and 36.3% (4/11) had an abnormal result respectively. CONCLUSION: This case series expands our knowledge of the prenatal presentation of 47, XXY by identifying first and second trimester fetal sonographic abnormalities. Prenatal identification of this condition enables accurate counseling, focused prenatal management, and early postnatal interventions to ameliorate some of the known complications.

Metabolomics in Placental Tissue from Women Living with HIV.

It is unknown whether antiretroviral (ARV) drugs in women living with HIV (WLHIV) are associated with mitochondrial toxicity and altered fat oxidation and branched-chain amino acid metabolism in the placenta and fetus. Immediately after delivery, we froze placental biopsies from 20 WLHIV and 20 matched uninfected women. We analyzed global biochemical profiles using high-performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We used t-tests, principle component analysis, hierarchical clustering, and random forest analysis (RFA) in our analysis. Twelve WLHIV were on protease inhibitors, six on non-nucleoside reverse inhibitors, and two on integrase strand inhibitors with optimized backbone. Mean birth weight of HIV-exposed neonates was significantly lower than unexposed neonates (3,075 g vs. 3,498 g, p = .01) at similar gestational age. RFA identified 30 of 702 analytes that differentiated the placental profiles of WLHIV from uninfected women with 72.5% predictive accuracy. Placental profiles of non-nucleoside reverse transcriptase inhibitor (NNRTI)-treated WLHIV exhibited lower levels of amino acids, including essential and branched-chain amino acids, and some medium-chain acylcarnitines. Placental metabolism may be altered in WLHIV, possibly associated with ARV exposure. The lower birth weight among neonates of WLHIV suggests the need for further studies considering potential deleterious effects of altered placenta metabolism on fetal growth and development.

Postpartum Hemorrhage in Patients with Type 1 von Willebrand Disease: A Systematic Review.

Type 1 von Willebrand disease (VWD) is the most common subtype of VWD, comprising 75% of VWD patients. We provide a systematic review of type 1 VWD in pregnancy. Our objective was to evaluate the rate of postpartum hemorrhage (PPH) in patients with known type 1 VWD. The primary outcome was rate of PPH. Primary PPH was defined as a cumulative blood loss ≥1,000 mL, or blood loss accompanied by signs and symptoms of hypovolemia within 24 hours postpartum or requiring blood products. Secondary PPH was defined as significant bleeding 24 hours to 12 weeks postpartum. Relevant articles published in English pertaining to VWD and pregnancy were identified without any time or study limitations. Seven articles (n = 144 pregnancies) met inclusion criteria. The rate of primary PPH was 4/144 (2.8%). The secondary PPH rate was reported in four studies, and occurred in 7/48 pregnancies (14.6%), ranging from 2 to 19 days postpartum. In conclusion, according to this systematic review, the frequency of primary PPH in pregnancies with known type 1 VWD is 2.8%. This is similar to the overall PPH rates of 3% reported in the literature. Although the sample size was small, secondary PPH occurred in almost 15% of pregnancies, while in the overall obstetrical population this occurs in approximately 1% of cases. Patients with known type 1 VWD may not be at increased risk of primary PPH, though they appear to bear increased risk of secondary PPH.

High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study.

PURPOSE: Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup. METHODS: Participants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records. RESULTS: Twenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1). CONCLUSION: The etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.

Type 2B von Willebrand Disease in Pregnancy: A Systematic Literature Review.

Our objective was to review the maternal characteristics and obstetric complications in women with type 2B von Willebrand disease (VWD). A systematic literature search was conducted using PubMed, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. We included all publications that addressed type 2B VWD in pregnancy. Our primary and secondary outcomes were incidence of postpartum hemorrhage (PPH) and incidence of thrombocytopenia in pregnancy. Two reviewers independently identified eligible studies and abstracted data including maternal characteristics, hematologic characteristics, treatment, and delivery outcomes. Twenty studies met inclusion criteria. There were 27 women (32 pregnancies) with type 2B VWD. Primary PPH was reported in 9/20 women (45%) and secondary PPH was reported in 6/13 women (46%). Thrombocytopenia in pregnancy was present in 27/28 women (96%); 23/27 women (85%) had platelet count <100 × 109/L, mean 33.7 ± 22.7 × 109/L. Factor concentrate treatment was administered before delivery (n = 16) and postpartum (n = 18), some women received both. Seventeen deliveries required blood products postpartum with 13/17 (76%) platelet transfusions and 6/17 (35%) red blood cell transfusions. No maternal mortality was reported. Women with type 2B VWD have significant morbidity in pregnancy related to high incidence of severe thrombocytopenia and primary and secondary PPH.

Type 3 von Willebrand Disease in Pregnancy: A Systematic Literature Review.

OBJECTIVE: von Willebrand disease (VWD) is a hereditary bleeding disorder. Type 3 VWD is the most severe and rare phenotype that presents many challenges for management of pregnant women. The aim of this study was to review the maternal characteristics and complications in pregnant women with Type 3 VWD. STUDY DESIGN: A systematic literature search was performed to include all publications that address Type 3 VWD in pregnancy. RESULTS: Thirteen studies met the inclusion criteria. There were 28 pregnancies with Type 3 VWD in 17 women. All were diagnosed with Type 3 VWD prior to pregnancy. Concentrate treatment was administered before delivery for 19 pregnancies and postpartum for 26 pregnancies. Eight pregnancies required blood products postpartum. Primary postpartum hemorrhage (PPH) was reported in 48% (10/21) and secondary PPH was reported in 56% (5/9). Secondary PPH occurred between 7 and 22 days. No study reported hysterectomies, intensive care unit admissions, or maternal mortality. All 28 pregnancies resulted in 28 live births at term. CONCLUSION: Our review highlights the maternal outcomes in patients with Type 3 VWD and the different approaches in management during pregnancy and delivery. Despite prior knowledge of this bleeding disorder, PPH was still a significant complication.

A systematic review of monogenic etiologies of nonimmune hydrops fetalis.

Hydrops fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and monogenic disorders. Despite this, the clinical workup typically evaluates limited genetic targets. To support broader molecular testing of pregnancies with HF, we cataloged the spectrum of monogenic disorders associated with nonimmune hydrops fetalis (NIHF). We performed a systematic literature review under PROSPERO tag CRD42018099495 of cases reporting NIHF meeting strict phenotypic criteria and well-defined genetic diagnosis. We ranked the evidence per gene based on number of reported cases, phenotype, and molecular/biochemical diagnosis. We identified 131 genes with strong evidence for an association with NIHF and 46 genes with emerging evidence spanning the spectrum of multisystem syndromes, cardiac disorders, hematologic disorders, and metabolic disorders. Several genes previously implicated with NIHF did not have any reported cases in the literature with both fetal hydrops and molecular diagnosis. Many genes with strong evidence for association with NIHF would not be detected using current sequencing panels. Nonimmune HF has many possible monogenic etiologies, several with treatment implications, but current diagnostic approaches are not exhaustive. Studies are needed to assess if broad sequencing approaches like exome sequencing are useful in clinical management of HF.

Pregnancy management in a patient with stickler syndrome.

BACKGROUND: Stickler syndrome is a collagen disorder that can affect multiple organ systems. It is characterized by ocular abnormalities, hearing loss, midfacial hypoplasia, hypermobility, and joint abnormalities. The phenotypic expression of Stickler syndrome can vary among those affected. Since Stickler syndrome is a collagen disorder, it is possible to expect pregnancy complications similar to those reported in other collagen disorders. To our knowledge, there is only one case report in the literature on the management of pregnancy and delivery of a patient with Stickler syndrome. METHODS/CASE REPORT: A 37-year-old primigravid woman with a diagnosis of Stickler syndrome presented at 9 weeks gestation for prenatal genetic consultation. At 26, the patient had prophylactic laser therapy for lattice degeneration of the retina. At 32, she was found to be heterozygous for the c.1527 G>T variant in the COL2A1 gene, which is associated with ocular abnormalities and autosomal dominant form of Stickler syndrome. Subsequently, she desired to pursue prenatal diagnostic testing for the familial variant. The patient voiced that the results would impact pregnancy management. Amniocentesis was performed at 16 weeks gestation. Results were negative for the maternal COL2A1 variant. Karyotype was normal (46, XX). RESULTS: A multidisciplinary team using a patient-centered approach including obstetrics, ophthalmology, maternal-fetal medicine, and genetics determined that there were no contraindications for vaginal delivery. At 39 weeks, the patient underwent spontaneous vaginal delivery with no complications. CONCLUSION: There is a paucity of data available regarding the maternal outcomes of women affected with collagen disorders, especially Stickler Syndrome. This case highlights the importance of accurate genetic diagnosis in the prenatal period and provides information to physicians caring for patients with Stickler syndrome.

Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study.

OBJECTIVES: Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution. METHODS: We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed. RESULTS: Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05. CONCLUSION: The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.

Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review.

Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF) including congenital disorders of glycosylation (CDG). Recognition of CDG in NIHF is challenging. This study reviews prenatal and neonatal characteristics of CDG presenting with NIHF. A systematic literature search was performed. Thirteen articles met the inclusion criteria. Twenty-one cases with NIHF associated with a CDG were reported. There were 17 live births, three pregnancy terminations, and one fetal demise. Timing of CDG diagnosis was reported mostly postnatally (90%; 10/11). Postnatal genetic testing was reported in 18 patients; three patients were diagnosed by isoelectric focusing of serum transferrin that showed a type 1 pattern. The genes reported for CDG with NIHF for 15 distinct families include: PMM2 in 47% (7/15), ALG9 in 20% (3/15), ALG8 in 13% (2/15), ALG1 in 7% (1/15), MGAT2 in 7% (1/15), and COG6 7% (1/15). In our review, 81% (17/21) reported facial dysmorphism, 52% (11/21) reported CNS abnormalities, most commonly cerebellar atrophy (64%; 7/11), and 38% (8/21) reported cardiovascular abnormalities, most commonly hypertrophic cardiomyopathy (63%; 5/8). Among live births, 71% (12/17) infants died at a median age of 34 days (range 1-185). Thrombocytopenia was reported in 53% (9/17) patients. Of those who survived past the neonatal period, 80% (4/5) had significant reported developmental delays. CDG should be on the differential diagnosis of NIHF in the presence of cerebellar atrophy, hypertrophic cardiomyopathy, or thrombocytopenia. Our review highlights the poor prognosis in infants with NIHF due to CDG and demonstrates the importance of identifying these disorders prenatally to guide providers in their counseling with families regarding pregnancy management. SYNOPSIS: Poor prognosis in fetuses and infants with nonimmune hydrops fetalis due to congenital disorders of glycosylation highlights the importance of prenatal diagnosis of this disorder.

Association of MicroRNAs with the Clinicopathologic Characteristics of Ependymoma.

The current management of ependymoma is wrought with limitations. Molecular classification is a promising development. MicroRNA (miRNA) deregulation is associated with human cancer and may be a means of molecular classification. The aim of our study is to investigate the association of miRNA expression with the clinicopathologic characteristics of ependymoma. Twenty-two samples were clinically annotated. Histologic features were reassessed and the expression of Ki-67, cyclin D1, and nestin was examined. The expression of 84 stem cell-related miRNAs was profiled. The ΔΔCT method and a Student's t test were used to compute fold changes and P values, respectively. Our analysis revealed 24 statistically significant associations. We identified seven site-specific miRNAs. The pattern of expression was variable in each anatomic site. In addition, we identified six candidate recurrence biomarkers, all of which were overexpressed in recurrent cases. All three grade-related miRNAs were underexpressed in anaplastic samples. Two miRNAs each were underexpressed in samples immunoreactive to Ki-67 and cyclin D1. No miRNAs were differentially expressed between nestin-negative and nestin-positive samples. In conclusion, molecular alterations in ependymoma involve miRNAs. In our report, we review the level of evidence for the biomarker candidacy of identified miRNAs. Confirmatory studies are necessary to establish robust biomarkers for the clinical management of ependymoma. Proteins regulated by differentially expressed miRNAs are additional candidate biomarkers and may offer targets for novel therapeutic interventions.