Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.

Obstetricians' views on the ethics of cardiac surgery for newborns with common aneuploidies.

OBJECTIVE: To examine whether obstetricians think that cardiac surgery is ethical in babies with common aneuploidies and whether insurance companies should be required to pay for these surgeries. STUDY DESIGN: A survey was e-mailed to 2897 OB-GYNs, and 898 (31%) actively practicing obstetricians responded to the survey. Respondents were asked whether it is ethical to offer cardiac surgery for babies with heart defects diagnosed with trisomies 21, 18, and 13 and Turner syndrome and whether insurance companies should be required to pay for such surgeries in cases of trisomy 18 or 13. Chi-square tests were utilized to compare responses by using an alpha level of .05. RESULTS: Most obstetricians thought that offering cardiac surgery was ethical if the baby had trisomy 21 or Turner syndrome (94%), but not trisomy 18 or 13 (75%). Most obstetricians (69%) thought that insurance companies should not be legally required to pay for cardiac surgery for the latter group. CONCLUSION: Obstetricians were more likely to think cardiac surgery was ethical if the prognosis or the outcome was good. Most respondents did not think that insurance companies should be required to subsidize the cost of cardiac surgeries for all babies with trisomy 18 or 13.

The utilization and choices of aneuploidy screening in a midwestern population.

The types, interpretation, and use of first- and second-trimester aneuploidy screening are often unclear for many women. This impairs appropriate decision making and understanding of the implications of prenatal genetic testing options. The purpose of this study was to examine the utilization of Stepwise Sequential screening in our Midwestern population, demographic factors associated with choice of screening and method of risk reporting and it's potential impact on women's choices. First trimester screening was performed for 2,634 women during the study period. Results were not reported or "framed" as "positive" or "negative". Rather, the specific age-risk and screen-risk for T21 were relayed, along with options for follow-up Stepwise Sequential screening and invasive testing. Nearly 80 % of women declined Stepwise Sequential screening. Minorities and women of lower education were least likely to pursue further screening. Less than 4 % of the study population elected invasive testing. First trimester screening was associated with a 53 % reduction in amniocenteses and 20 % fewer CVS's compared to pre-first trimester screening availability. Reporting age-and screen-risks for T21, rather than classifying results as "positive" or "negative" based on a pre-determined threshold, was associated with a low uptake of further testing.

Inclusion of librarians and information professionals in Canadian knowledge synthesis grant funding.

Introduction: Librarians continually advocate for the expertise they can bring to knowledge synthesis research projects. Professional associations like the Canadian Health Libraries Association aim to promote librarians and information professionals as partners in health research. This push for representation must happen at a policy level to enact change. To that purpose, we explored the degree to which the inclusion of librarians and information professionals is represented at the funding level by healthcare research organizations in Canada. Methods: We used a list of health research funding agencies generated from Scopus searches and an independent search of Canadian health research institutions, governmental health authorities, professional associations, and research-oriented universities to identify research grants designed for knowledge synthesis research. We examined these grants to determine whether they require or specifically mention librarians in their eligibility criteria. Results: Of the 14 knowledge synthesis grants we identified, only one required a health librarian as a member of the research team in the grant eligibility criteria. Four grants "strongly recommended" the inclusion of librarians on the research team, though this inclusion was not a contingency for funding. Discussion: Most knowledge synthesis grants in Canada do not require, recommend, or mention librarians as members of the research or authorship team. Evidence suggests that librarian involvement substantially improves the quality of knowledge synthesis research projects; it would therefore benefit both librarians and knowledge synthesis work to advocate for librarian involvement as a contingency for grant funding.

Efficiency of first-trimester growth restriction and low pregnancy-associated plasma protein-A in predicting small for gestational age at delivery.

OBJECTIVE: To evaluate the efficiency of first-trimester fetal growth restriction (FGR), low pregnancy-associated plasma protein A (PAPP-A), and their combination for predicting small for gestational age (SGA) at delivery. METHODS: Retrospective cohort study of women undergoing first-trimester aneuploidy screening. Fetal crown-rump lengths (CRLs) were at 10 to 14 weeks' gestation and converted to gestational age adjusted Z-scores. Low PAPP-A was defined as levels<5th percentile for GA. Receiver-operating characteristic curves were used to assess screening efficiencies. RESULTS: Among 3269 pregnancies meeting the inclusion criteria 185 (5.7%) infants were SGA. CRL Z-score< -1.0 standard deviation was identified as the optimal definition of early FGR. Using either CRL Z-score< -1.0 standard deviation or PAPP-A<5th percentile had the highest sensitivity (33%) with a specificity of 82.1% when screening for SGA. Using a combination resulted in an increased association (adjusted odds ratio 4.23[confidence interval 1.37-13.03]) at the expense of significantly reduced sensitivity (3.13%). CONCLUSIONS: First-trimester FGR and PAPP-A<5th percentile are associated with delivery of an SGA infant. Neither of these parameters or the combination of the two are sufficient powerful predictors of SGA to be clinically useful screening tools.

The genetic sonogram: comparing the use of likelihood ratios versus logistic regression coefficients for Down syndrome screening.

OBJECTIVES: The purpose of this study was to compare the screening efficiency for Down syndrome using likelihood ratios versus logistic regression coefficients. METHODS: We conducted a retrospective study of women at increased risk for Down syndrome referred for a second-trimester genetic sonogram. Likelihood ratios were calculated by multiplying the risk ratio from maternal serum screening by the likelihood ratios of sonographic markers. Logistic regression coefficients were calculated using a formula derived from ß coefficients generated from a multivariable logistic regression model. The screening efficiency of both methods was tested in an independent population of patients. The McNemar test was used to compare the predictive ability of the two methods. RESULTS: In the validation population, the use of likelihood ratios had an area under the receiver operator characteristic curve of 0.90 for Down syndrome detection, whereas the use of logistic regression coefficients had an area under the curve of 0.86. Adopting a risk cutoff point of 1/270, the sensitivity of likelihood ratios was 77.4% (95% confidence interval [CI], 58.9%-90.4%) with a false-positive rate of 17.9% (95% CI, 15.0%-21.1%), whereas the sensitivity of logistic regression coefficients was 93.5% (95% CI, 78.6%-99.2%) with a false-positive rate of 34.6% (95% CI, 30.9%-38.4%). There was significant difference in screening efficiency for Down syndrome detection between the two methods (exact McNemar χ(2), P < .001 ). CONCLUSIONS: With a slight reduction in the Down syndrome detection rate, the use of the likelihood ratio approach was associated with a significantly lower false-positive rate compared with the logistic regression approach.

The impact of assisted reproductive technology on the association between first-trimester pregnancy-associated plasma protein a and human chorionic gonadotropin and adverse pregnancy outcomes.

We evaluated the impact of assisted reproductive technology (ART) on the association between first-trimester pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (ß-hCG) and adverse pregnancy outcomes. PAPP-A and ß-hCG levels were obtained between 11 and 13 (6)/ (7) weeks' gestation and converted to multiples of the median (MoM). MoM < 5th percentile was defined as low PAPP-A or ß-hCG and those > 90th percentile as high. Adverse outcomes included small-for-gestational-age (SGA) infants, preeclampsia, pregnancy loss, and preterm delivery (PTD). Univariate and multivariate analyses were used to estimate the association. Of 4000 women meeting the inclusion criteria, 265 (7.6%) pregnancies were conceived by ART. ART pregnancies with low PAPP-A had a higher risk of having an SGA infant (odds ratio [OR] = 4.1, 95% confidence interval [CI] 1.2, 14.0) or PTD < 32 weeks (OR = 5.3, 95% CI 1.5, 18.6) compared with non-ART pregnancies with low PAPP-A (OR = 2.8, 95% CI 1.7, 4.7; OR = 3.9, 95% CI 2.1, 7.0, respectively). High PAPP-A was associated with pregnancy loss (OR = 6.1, 95% CI 1.1, 33.7) in ART pregnancies. Low ß-hCG was associated with increased risk for PTD only in ART pregnancies (OR = 8.3, 95% CI 1.9, 35.9) for PTD < 37 weeks (OR 6.1, 95% CI 1.6, 23.0) for PTD < 35 weeks and (OR = 10.8, 95% CI 2.7, 43.7) for PTD < 32 weeks. High ß-hCG was associated with increased risk for SGA (OR = 1.6, 95% CI 1.0, 2.5) and PTD < 37 weeks (OR = 1.4, 95% CI 1.0, 1.9) in non-ART pregnancies. The association between PAPP-A and ß-hCG with adverse pregnancy outcomes is influenced by the mode of conception.

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.