Transforming congenital heart disease management: Advances in fetal cardiac interventions.

This review addresses the transformative advancements in fetal cardiac interventions (FCI) for congenital heart diseases (CHD), with a particular focus on aortic stenosis with evolving hypoplastic left heart syndrome, pulmonary atresia with an intact ventricular septum, and HLHS with an intact atrial septum (HLHS-IAS). We outline the specific FCI techniques employed, the refined criteria for selecting appropriate fetal and maternal candidates, and the promising yet varied outcomes associated with these procedures. Procedural strategies and clinical decision-making are examined as we take into account the fetal pathophysiology and the benefits and risks of early intervention. We highlight the role of multidisciplinary teams in improving technical success and managing immediate procedural complications, which have led to significant improvements in procedural outcomes. Additionally, the review discusses the long-term outcomes, challenges, and future research directions in FCI, emphasizing the necessity for continuous innovation and collaboration across specialties to advance the management of CHD. The integration of new technologies and research findings holds the promise of further enhancing FCI success rates and patient outcomes.

Postnatal genetic testing on cord blood for prenatally identified high-probability cases.

OBJECTIVE: To evaluate the utility of postnatal genetic testing on umbilical cord blood (CB) for prenatally identified high-probability fetuses. METHOD: CB for genetic testing was offered to individuals who met one of the following criteria: (i) fetal anomaly, (ii) positive non-invasive prenatal screening by cfDNA or biochemical analysis, or (iii) family history. Individuals with diagnostic testing, but not microarray, were also included when recommended by society guidelines. CB was collected at Brigham and Women's and Emerson Hospitals between 2016 and 2021. RESULTS: 448 individuals consented for cord blood testing (370 (82.6%) for fetal anomalies, 51 (11.4%) for high-probability cfDNA, and 27 (6.0%) for family history) and a total of 393 (87.7%) samples were analyzed. Genetic testing yielded a diagnosis in 92 (23.4%) neonates by karyotype (n = 37), chromosomal microarray (CMA) (n = 32), and other molecular analysis (n = 23). Testing averaged 10.3 days (range 1-118 days). 68 (73.9%) diagnoses potentially impacted neonatal management. MCC could not be definitively excluded in only 1.4% (6/418) of samples. CONCLUSION: Prenatal identification of high-probability fetuses and genetic testing on CB facilitates timely genetic diagnoses and neonatal management. Testing provides reassurance and reduces a postnatal diagnostic odyssey for high-probability neonates.

Single gene non-invasive prenatal screening for autosomal dominant conditions in a high-risk cohort.

PURPOSE: To determine the utility of single gene non-invasive prenatal screening (NIPS-SGD) in a high-risk reproductive genetics clinic. METHODS: A clinical pilot for NIPS-SGD was conducted from March 2020 to November 2021. A NIPS-SGD panel assessing pathogenic variants in 30 genes was offered to pregnant individuals for the following indications: (1) advanced sperm age ≥40 years, (2) nuchal translucency (NT) ≥ 3.5 mm, (3) fetal anomaly, or (4) family history of a condition covered by the panel. Diagnostic testing was offered concurrently. RESULTS: NIPS-SGD was ordered for 253 individuals: 88 (34.8%) for fetal anomalies, 96 (37.9%) for advanced sperm age, 37 (14.6%) for increased NT, and 5 (2.0%) for family history. Among 228 (90.1%) completed tests, 8 (3.5%) were positive. Diagnostic testing for 78 individuals revealed no false positive or negative results. Of 41 (25.9%) individuals who received a molecular diagnosis, 34 (82.9%) were outside the scope of NIPS-SGD. Positive NIPS-SGD altered medical management in five cases. CONCLUSIONS: NIPS-SGD in a high-risk population can lead to earlier prenatal diagnosis, enhanced surveillance, and targeted genetic analysis, but should not replace clinically indicated diagnostic testing. Potential incidental findings include parental diagnoses and misattributed parentage.

Hemodynamic and anatomic changes after fetal aortic valvuloplasty are associated with procedural success and postnatal biventricular circulation.

BACKGROUND: There are minimal data characterizing the trajectory of left heart growth and hemodynamics following fetal aortic valvuloplasty (FAV). METHODS: This retrospective study included patients who underwent FAV between 2000 and 2019, with echocardiograms performed pre-FAV, immediately post-FAV, and in late gestation. RESULTS: Of 118 fetuses undergoing FAV, 106 (90%) underwent technically successful FAV, of which 55 (52%) had biventricular circulation. Technically successful FAV was associated with improved aortic valve growth (p < 0.001), sustained antegrade aortic arch (AoA) flow (p = 0.02), improved mitral valve (MV) inflow pattern (p = 0.002), and favorable patent foramen ovale (PFO) flow pattern (p = 0.004) from pre-FAV to late gestation. Compared to patients with univentricular outcome, patients with biventricular outcome had less decrement in size of the left ventricle (LV) (p < 0.001) and aortic valve (p = 0.005), as well as more physiologic PFO flow (p < 0.001) and antegrade AoA flow (p < 0.001) from pre-FAV to late gestation. In multivariable analysis, echocardiographic predictors of biventricular outcome were less decline in LV end diastolic dimension (p < 0.001), improved PFO flow (p = 0.004), and sustained antegrade AoA flow (p = 0.002) from pre-FAV to late gestation. CONCLUSION: Stabilization of left heart growth and improved hemodynamics following successful FAV through late gestation are associated with postnatal biventricular circulation.

Counseling for personal health implications identified during reproductive genetic carrier screening.

OBJECTIVE: Preconception and prenatal carrier screening is designed to provide reproductive risk information, but carriers for some autosomal recessive or X-linked conditions also have personal health risks. This study investigated the prevalence of and inclusion of personal health implications in pre- and post-test counseling. METHODS: Twelve genetic conditions with personal health risks for carriers included on carrier screening panels but not otherwise screened routinely were identified (e.g., Gaucher disease with Parkinson's disease risk). A retrospective review was performed of patients with a positive carrier screen for one of these conditions at our center from 2012 to 2019. RESULTS: Of 6147 individuals that had carrier screening for one of the twelve conditions, 96 (1.56%) did not report a known family history and screened positive for one of the conditions. Testing was ordered largely by reproductive endocrinologists (51.0%) and genetic counselors (35.4%). Most individuals did not receive pre- (96.8%) or post-test (64.6%) counseling about personal health risks. Post-test counseling was performed principally by genetic counselors (97.1%). For carriers of conditions with guidelines for specialist referral, most individuals (75.9%) were referred. CONCLUSION: Expanded genetic carrier screening increasingly identifies individuals with personal health implications, but patients are frequently not counseled before or after testing. These findings stress the importance of developing guidelines for practitioners about expanded carrier screening counseling and follow-up.

Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing.

PURPOSE: Copy-number variant (CNV) assessment is recommended for patients undergoing prenatal diagnostic testing. Noninvasive screening tests have not been extensively validated for CNV detection. The objective of this study was to compare the ability of genome-wide noninvasive prenatal screening (NIPS) to chromosomal microarray to detect clinically significant findings. METHODS: We prospectively enrolled 198 subjects at the time of consent for diagnostic prenatal testing. Genome-wide NIPS results were compared with diagnostic testing results to assess NIPS test performance (n = 160, 38 subjects without microarray results excluded). Cohen's kappa statistic was used to assess test agreement. RESULTS: Genome-wide NIPS did not detect clinically significant chromosomal abnormalities at the same rate as diagnostic testing, κ = 0.75 (95% confidence interval [CI], 0.62-0.87). When excluding CNVs <7 Mb and findings outside the limits of genome-wide NIPS, test agreement improved, κ = 0.88 (0.79-0.97) driven by agreement for common aneuploidies (κ = 1.0). However, among patients with an abnormal fetal survey, agreement was only fair, κ = 0.38 (0.08-0.67). CONCLUSION: While NIPS is an excellent screening test for common aneuploidies, genome-wide NIPS misses clinically significant findings detected on routine diagnostic testing. False positive and false negative cases highlight the importance of pretest counseling regarding NIPS limitations, especially in the setting of fetal anomalies.

Gene and Stem Cell Therapies for Fetal Care: A Review.

Importance: Gene and stem cell therapies have become viable therapeutic options for many postnatal disorders. For select conditions, prenatal application would provide improved outcomes. The fetal state allows for several theoretical advantages over postnatal therapy, including immune immaturity and cellular niche accessibility. Observations: Advances in prenatal diagnostic accuracy and surgical precision, as well as improvements in stem cell and gene therapy methods, have made prenatal gene and stem cell therapy realistic. Studies in mouse models and early human trials demonstrate the feasibility of these approaches. Additional efforts are under way to streamline fetal applications of stem cell and gene therapy while carefully considering best ethical practice and following established regulatory pathways. Conclusions and Relevance: Fetal stem cell and gene therapy bring important therapeutic opportunities for select disorders that present in the fetal and neonatal periods. While this field is in its infancy, these therapies are starting to be available clinically, and clinicians should be aware of their benefits and challenges.

Noninvasive prenatal testing: from aneuploidy to single genes.

Noninvasive prenatal testing has undergone rapid advances in the last few years. Although researchers have long known about circulating pregnancy-based cell-free fragments of DNA in maternal plasma, it was the introduction of massively parallel sequencing that allowed noninvasive prenatal testing to become a widely used clinical test. This review will begin with an in-depth analysis of the use of noninvasive prenatal testing for aneuploidy, including common causes for inaccurate and/or discordant results. It will also review the ongoing expansion of noninvasive prenatal testing to include copy number variants and select single-gene disorders. Finally, integrated throughout the review is a comparison of noninvasive prenatal testing to more traditional screening methods along with some medical and ethical implications of the widespread use of this new technology.

Fetal cardiac intervention-Perspectives from a single center.

Fetal cardiac intervention was first proposed in the early 1990s to impact cardiac development and survival of fetuses with fetal aortic stenosis and evolving hypoplastic left heart syndrome (HLHS). Although initial attempts of fetal aortic valvuloplasty were unsuccessful and carried a high rate of morbidity and mortality, our collaborative group at the Brigham and Women's Hospital and Boston Children's Hospital have reinvigorated the procedure using improvements in imaging, anesthesia, balloon catheters, and surgical techniques. Two decades of experience have now allowed us to document the safety of in utero intervention and to achieve a better understanding of the impact of midgestation intervention on developing HLHS. Research into underlying genetics, predictive biomarkers, and ways to incorporate stem cell technology will hopefully allow us to further refine the procedure to most benefit children with this historically lethal disease.

Antepartum management and obstetric outcomes among pregnancies with Down syndrome from diagnosis to delivery.

OBJECTIVE: Little is known about the obstetric care of an ongoing pregnancy with trisomy 21. We sought to ascertain an obstetric profile for pregnancies with Down syndrome to help guide prenatal management. METHOD: Pregnancies managed for delivery with trisomy 21 between 2003 and 2014 were analyzed. We reviewed demographic data, diagnostic testing, prenatal surveillance, obstetric outcomes, and placental pathology. T-test, chi-squared test, and Fisher correction were used as indicated. RESULTS: Sixty-eight pregnancies were identified, and four women (5.9%) experienced a loss during the pregnancy. Among the remaining 64 pregnancies, the average gestational age at delivery was 36.9 weeks, growth restriction was present in 12 (17.5%), and major anomalies were present in 51 (75.0%). Delivery was undertaken for non-reassuring fetal surveillance in 35.9% of the pregnancies; 93% of which represented a change from prior reassuring surveillance and 52.6% of which demonstrated histopathologic evidence of placental insufficiency. None among increased maternal age, the presence of an anomaly, or growth restriction were significantly more common in the group with non-reassuring surveillance. CONCLUSION: There are high rates of fetal growth restriction, delivery for non-reassuring fetal status, and evidence of placental insufficiency among affected pregnancies, suggesting a role for antepartum surveillance. © 2017 John Wiley & Sons, Ltd.

How Accurate Is the Dating of Scheduled 39-Week Deliveries?

OBJECTIVE: We assessed the impact of a policy preventing scheduled repeat cesarean deliveries at less than 39 weeks, accounting for potential inaccuracies in pregnancy dating. STUDY DESIGN: We analyzed a cohort of repeat cesarean deliveries before and after the policy change and used chi-square testing to compare the proportion of deliveries at less than 39 weeks. We assessed whether the reduction in early-term deliveries was different if the gestational age was based on the documented estimated date of delivery (EDD) as compared with best obstetric dating. RESULTS: Our cohort consisted of 213 women; 112 before the policy change and 101 after. Using the EDD assigned at delivery, there was a 12.1% absolute decrease in scheduled deliveries at less than 39 weeks (25.0-12.9%; p = 0.025). However, using the EDD by best obstetric dating, there was no significant change (32.1-25.7%; p = 0.305). Of the 85 discrepant EDDs, providers were more likely to assign an earlier EDD (63.5%; p = 0.013). CONCLUSION: Our institution's policy change led to a 12.1% absolute reduction in documented, scheduled early-term deliveries, however only a 6.4% absolute decline using best obstetric dating. Policy initiatives to reduce early-term deliveries should consider the source and accuracy of the assigned pregnancy dating.

Can enriching emotional intelligence improve medical students' proactivity and adaptability during OB/GYN clerkships?

OBJECTIVE: The purpose of this pilot study was to examine our hypothesis that enriching workplace emotional intelligence through resident coaches could improve third-year medical students' adaptability and proactivity on the Obstetrics and Gynecology clerkship. METHODS: An observational pilot study was conducted in a teaching hospital. Fourteen 3rd year medical students from two cohorts of clerkships were randomly divided into two groups, and equally assigned to trained resident coaches and untrained resident coaches. Data was collected through onsite naturalistic observation of students' adaptability and proactivity in clinical settings using a checklist with a 4-point Likert scale (1=poor to 4=excellent). Wilcoxon rank-sum test was used to compare the differences between these two groups. RESULTS: A total of 280 data points were collected through onsite observations conducted by investigators. All (n=14) students' adaptability and proactivity performance significantly improved from an average of 3.04 to 3.45 (p=0.014) over 6-week clerkship. Overall, students with trained resident coaches adapted significantly faster and were more proactive in the obstetrics and gynecology clinical setting than the students with untrained coaches (3.31 vs. 3.24, p=0.019). CONCLUSIONS: Findings from our pilot study supported our hypothesis that enriching workplace emotional intelligence knowledge through resident coaches was able to help medical students adapt into obstetrics and gynecology clinical settings faster and become more proactive in learning. Clerkship programs can incorporate the concept of a resident coach in their curriculum to help bridge medical students into clinical settings and to help them engage in self-directed learning throughout the rotation.

Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia.

PROBLEM: Severe preeclampsia has been independently linked to complement dysregulation and angiogenic imbalance; however, the relationship between complement and angiogenic factors in human pregnancy is unclear. METHOD OF STUDY: Utilizing existing biomarkers, our study sought to better understand this relationship in active disease. We performed a case-control study, enrolling 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension. Levels of complement components (C3a, C5a, and C5b-9) and angiogenic markers [basic fibroblast growth factor (bFGF), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)] were measured simultaneously. RESULTS: Compared to both hypertensive and non-hypertensive controls, severe preeclampsia was associated with increased plasma sFlt-1, decreased plasma VEGF and PlGF, decreased urinary PlGF, and increased urinary C5b-9. Urinary marker C5b-9 correlated strongly with the anti-angiogenic condition. In subjects with detectable urinary excretion of C5b-9, median plasma levels of sFlt-1 were significantly greater (32,029 versus 4556 pg/mL, P < 0.0001) and levels of PlGF (15.6 versus 226 pg/mL, P < 0.0001) and VEGF (119 versus 153 pg/mL, P = 0.001) were significantly lower. CONCLUSION: More so than plasma complement markers, urinary C5b-9 may a useful measure to link complement dysregulation with angiogenic imbalance in severe preeclampsia.

What is the optimal treatment for obese patients with advanced ovarian carcinoma?

OBJECTIVE: The purpose of this study was to compare primary debulking surgery (PDS) vs neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) among obese patients. STUDY DESIGN: Medical records of patients with a body mass index (BMI) of ≥30 kg/m(2) with ovarian/fallopian tube/primary peritoneal carcinoma between January 2005 and December 2010 were reviewed. Patients were separated by PDS or NACT-IDS. Preoperative characteristics, surgical procedures, and postoperative and oncologic outcomes were compared. RESULTS: Of 117 patients, 95 women (81.2%) underwent PDS, and 22 women (18.8%) underwent NACT-IDS. Patients who underwent NACT-IDS were more likely to have stage IV disease (63.6% vs 26.3%; P = .001) and a low surgical complexity score (n = 14; 63.6%). There were no other differences between groups with respect to preoperative characteristics or postoperative morbidity. Compared with the NACT-IDS group, the PDS group had an improved progression-free survival (PFS; 15 vs 11 months; P = .006) and overall survival (OS; 53 vs 32 months; P = .036). Seventy-eight patients (66.7%) had a BMI of 30-34.9 kg/m(2). Within this subset of obese patients, the PDS group had an improved PFS (15 vs 10 months; P = .011) and OS (58 vs 32 months; P = .033), compared with the NACT-IDS group. Among patients with a BMI of ≥35 kg/m(2), there was no difference in PFS (14 vs 12 months; P = .316) or OS (38 vs 32 months; P = .640) when the PDS and NACT-IDS groups were compared. CONCLUSION: Patients with a BMI of 30-34.9 kg/m(2) who undergo PDS have improved oncologic outcomes, compared with those women who undergo NACT-IDS. Patients with a BMI of ≥35 kg/m(2) who undergo PDS have similar oncologic outcomes to those who undergo NACT-IDS. Complication rates were similar at all BMIs, regardless of treatment approach.

Transitional cell carcinoma of the ovary: a case-control study.

OBJECTIVES: The aim of this study is to compare response to chemotherapy and survival between patients with transitional call carcinoma of the ovary (TCCO) and papillary serous ovarian cancer (PSOC). METHODS: We identified women with both pure and mixed TCCO who were treated between 2000 and 2010. Each case was matched to two women with PSOC by age, grade, stage, and year of diagnosis. Correlation between categorical variables was assessed with chi square test. The Kaplan-Meier survival analysis was used to generate overall survival data (OS). Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS: Eighty-one women diagnosed with TCCO were selected as cases and compared to 162 controls. Women with TCCO had a lower rate of platinum resistance compared to controls (9% vs. 25%; p=0.01). When multivariate logistic regression was used to control for other factors independently associated with platinum resistance, patients with TCCO had a significantly lower risk of platinum resistance compared to PSOC. Median progression-free survival was not significantly different (27 months vs. 22 months; p=0.15) for women with TCCO and PSOC, respectively. Median OS, however, was significantly different at 83 months vs. 52 months for the TCCO and PSOC groups, respectively (p=0.01). A Cox proportional hazards model identified optimal cytoreduction, transitional cell histology, age, stage, and platinum and paclitaxel chemotherapy as independent predictors of OS. CONCLUSIONS: Patients with TCCO are less likely to demonstrate resistance to platinum chemotherapy and have improved overall survival when compared to patients with PSOC.

Patterns of recurrence in patients treated with bevacizumab in the primary treatment of advanced epithelial ovarian cancer.

OBJECTIVE: The purpose of this study was to compare the distribution of the first site of recurrence in patients with epithelial ovarian cancer (EOC) who received first-line treatment with bevacizumab compared with patients who did not receive bevacizumab. METHODS: From the Cancer Registry database at our institutions, we identified a group of patients with recurrent EOC who underwent treatment from January 1, 2005, to December 31, 2010. Each patient record was evaluated to classify the site of first recurrence. Correlation between categorical variables was assessed with χ² test. RESULTS: Two hundred ninety-two patients with advanced EOC (stage III or IV) who originally responded to chemotherapy and had a recurrence were identified. Of these, 37 (12.5%) had received postoperative chemotherapy bevacizumab, and 255 (87.5%) did not. Compared with those not treated with bevacizumab, there was a lower incidence of liver recurrence (0% vs 9%; P = 0.05) and a higher rate of lung and/or pleural recurrence (22% vs 5%; P = 0.001) and recurrence at distant sites (22% vs 9%; P = 0.03) in patients who received bevacizumab. There was no difference in the incidence of ascites at the time of recurrence between these groups. CONCLUSIONS: Patients who received bevacizumab as part of primary treatment for EOC had a higher rate of lung and/or pleural recurrence and a lower rate of liver recurrence. There was no difference in the rate of ascites at the time of recurrence.