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.

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.

Fetal pharmacogenomics: A promising addition to complex neonatal care.

OBJECTIVE: Pharmacogenomics (PGx) characterizes genetic variation in medication response. 85-95% of the population carries actionable PGx variants. No prior studies have demonstrated the application and feasibility of PGx in prenatal testing. We assessed parental desire for PGx findings from fetal exome sequencing (ES), evaluated PGx variants, and reviewed implications for medically complex neonates. METHODS: A prospective cohort undergoing ES for nonimmune hydrops fetalis were offered PGx results as a secondary finding. Seven pharmacogenes with Level A evidence, defined by Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, were tested and reported to patients and referring providers. Medication administration records were reviewed. RESULTS: Most participants (36/40, 90%) desired PGx testing. 32/36 (89%) had potentially actionable PGx diplotypes in six genes: CYP2C19 (20/36, 56%), CYP2C9 (16/36, 44%), CYP2D6 (10/36, 28%), SLCO1B1 (13/36, 36%), TPMT (6/36, 17%), UGT1A1 (4/36, 11%). 12/13 (92%) live births had PGx variants. Neonatal chart review indicated that three medications with CPIC Level A evidence were administered to four neonates. None of the patients received a medication that aligned with an actionable pharmacogenetic variant as defined by Level A CPIC guidance. CONCLUSION: Most participants opted to receive PGx results. 89% had actionable variants, consistent with population estimates. Obtaining fetal PGx data is feasible for medically complex neonates. Further studies are needed for broad clinical application of PGx in fetuses with major congenital abnormalities. Our study demonstrates the potential of PGx as useful preemptive clinical information that could be obtained at the time of fetal exome sequencing for other indications. CLINICALTRIALS: gov Registration: NCT03911531.

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.

Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review.

We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed, Ovid, and clinicaltrials.gov were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, 22 case series with 2678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2663) in NIHF cases that were tested for any LSD, and 8.2% (177/2151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis, and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk.

Entertainment-Education Campaigns and COVID-19: How Three Global Organizations Adapted the Health Communication Strategy for Pandemic Response and Takeaways for the Future.

COVID-19 created a substantial set of challenges for health communication practitioners in the process of planning, implementing, and evaluating entertainment-education (EE) campaigns. EE is a theory and evidence-based communication strategy that employs entertainment media for educational messaging. Here, we briefly review EE campaigns in response to previous health emergencies and present three cases of EE responses to the COVID-19 pandemic from leading global organizations (PCI Media, BBC Media Action, and Sesame Workshop). Responses ranged from adaptation and re-distribution of existing content to creating new content under social-distancing restrictions and utilizing transmedia. These cases demonstrate that EE initiatives responding to future pandemics may be well served by starting with existing infrastructure to quickly build capacity, support, and trust; working with partners to tailor programs to the local context; and continuing to focus on good storytelling while simultaneously considering evolving media formats and theory.

Prospective Randomized Study Evaluating the Effects of Preoperative Opioid Counseling on Postoperative Opioid Use after Outpatient Lower Extremity Orthopaedic Surgery.

The objective of this study was to investigate the effect of standardized preoperative opioid counseling on postoperative opioid consumption for patients undergoing outpatient lower extremity orthopaedic surgery. Participating patients undergoing elective outpatient lower extremity orthopaedic surgery were randomized to either receive preoperative opioid counseling or not receive counseling (control group). Counseling was delivered via a five-minute pre-recorded standardized video preoperatively. Postoperatively, patients in both groups were queried for their postoperative pain experience, opioid consumption, non-opioid medication consumption, and any adverse effects related to their pain management experience. A total of 107 patients were studied, with 45 in the counseling group and 62 in the control group. Patients that received preoperative opioid counseling consumed on average 6.5 opioid pills postoperatively; the control group consumed 12.4 opioid pills (p = 0.008). Preoperative opioid counseling resulted in a statistically significant reduction in postoperative opioid consumption after outpatient lower extremity orthopaedic surgery. (Journal of Surgical Orthopaedic Advances 30(1):002-006, 2021).

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.

The Impact of COVID-19 on Inpatient Consultations and the Role of Telehealth: A Retrospective Cohort.

Falls in non-COVID-19-related hospital admissions during the pandemic affected the reasons for dermatology consultation and mode of consultation delivery. In order to assess the impact of the pandemic and the effects of telehealth on the inpatient dermatology service, we compared consultations completed between March 17, 2020 and October 31, 2020 with the same period of 2019. Dermatology received fewer consultations for management assistance during the pandemic, possibly due to patients with chronic dermatoses not meeting admission criteria or avoiding hospitalization. Consultations were also less likely to require laboratory work, imaging, and biopsies in 2020, potentially due to frequent consultation of benign conditions enabled by telehealth and stricter enforcement of only completing the biopsies necessary for acute inpatient management. Despite the shift toward remote consultations in 2020, the impact on diagnosis and management remained unchanged compared to 2019. Providers were less likely to document clinical improvement in 2020, potentially attributable to inferior communication regarding management recommendations or an increase in diagnoses not expected to improve. While remote consultations allowed dermatologists to provide comparable care during the pandemic, further research on clinical outcomes of remote consultations is required to maximize its benefits to patients and the healthcare system. (SKINmed. 2022;20:197-204).

Experiences of New Mothers During the Coronavirus Disease 2019 (COVID-19) Pandemic.

OBJECTIVE: To describe postpartum experiences of women who gave birth during the coronavirus disease 2019 (COVID-19) pandemic, to identify short-term and long-term opportunities to address maternal-child health during this pandemic. METHODS: This qualitative photo-elicitation study asked 30 women between 3 and 10 weeks postpartum to take photographs that encompassed their experience as a new mother during the pandemic. Two trained interviewers elicited elements of this experience using the photos as an anchor during virtual, hour-long interviews. Interview transcripts were analyzed using directed content analysis, including open coding to identify key ideas, codebook development, and codebook refinement. Half of transcripts were team coded to ensure coding accuracy. After coding, the study team organized codes to inform the development of an explanatory model. RESULTS: Interviews identified important stressors new mothers experienced that were worsened during the pandemic, namely fear, child care, older children, loss, isolation, and employment. Interviews also highlighted key support structures (self-care, interpersonal, and structural supports) that were at times helpful in alleviating stressors and at others were inadequate to counter stress and even enhanced stress. CONCLUSION: For postpartum individuals overall, the pandemic resulted in increased strain during an already stressful time. These findings demonstrate inadequacy of support systems for postpartum women and may highlight action items for stakeholders to improve postpartum care during the pandemic and in the future.

Prospective Randomized Study Examining Preoperative Opioid Counseling on Postoperative Opioid Consumption after Upper Extremity Surgery.

Background: Rates of opioid addiction and overdose continue to climb in the United States, increasing pressure on prescribers to identify solutions to decrease postoperative opioid consumption. Hand and upper extremity surgeries are high-volume surgeries with a predilection for inadvertent overprescribing. Recent investigations have shown that preoperative opioid counseling may decrease postoperative opioid consumption. In order to test this hypothesis, a prospective randomized trial was undertaken to determine the effect of preoperative opioid counseling on postoperative opioid consumption. Methods: Eligible patients undergoing outpatient upper extremity surgery were randomized to either receive preoperative opioid counseling or to receive no counseling. Surgeons were blinded to their patient's counseling status. Preoperatively, patient demographics, surgical and prescription details were recorded. Postoperatively, patients' pain experience including opioid consumption, pain levels, and satisfaction was recorded. Results: There were 131 total patients enrolled, with 62 in the counseling group and 69 in the control group. Patients receiving counseling consumed 11.8 pills compared to 17.4 pills in the control group (P = .007), which translated to 93.7 Morphine Equivalent Units (MEU) in the counseling group compared to 143.2 MEU in the control group (P = .01). There was no difference in pain scores at any time point between groups. Among all study patients a total of 3767 opioid pills were prescribed with approximately 50% left unused. Conclusion: Patients receiving preoperative counseling consumed significantly fewer opioids postoperatively. Inadvertant overprescribing remains high. Routine use of preoperative counseling should be implemented along with prescribing fewer opioids overall to prevent overprescribing.