Piloting a multidisciplinary approach to improve outcomes of fetal whole exome sequencing: An overview of workflow and case example.

INTRODUCTION: Whole exome sequencing (WES) has increasingly become integrated into prenatal care and genetic testing pathways. Current studies of prenatal WES have focused on diagnostic yield. The possibility of obtaining a variant of uncertain significance and lack of provider expertise are frequently described as common barriers to clinical integration of prenatal WES. We describe the implementation and workflow for a multidisciplinary approach to effectively integrate prenatal WES into maternal-fetal care to overcome these barriers. METHODS: A multidisciplinary team reviews and approves potential cases for WES. This team reviews WES results, reclassifying variants as appropriate and provides recommendations for postnatal care. A detailed description of this workflow is provided, and a case example is included to demonstrate effectiveness of this approach. Our team has approved 62 cases for WES with 45 patients ultimately pursuing WES. We have achieved a diagnostic yield of 40% and the multidisciplinary team has played a role in variant interpretation in 50% of the reported variants of uncertain significance. CONCLUSIONS: This approach facilitates communication between prenatal and postnatal care teams and provides accurate interpretation and recommendations for identified fetal variants. This model can be replicated to ensure appropriate patient care and effective integration of novel genomic technologies into prenatal settings.

Prenatally Diagnosed Posterior Urethral Valves: Ethical Dilemmas of Fetal Intervention.

Although anhydramnios due to in utero renal failure has traditionally been considered lethal, in utero interventions offer the potential for pulmonary survival. As fetal interventions become more common, questions arise about how to identify and counsel eligible candidates.  In this report we describe the presentation and management of a 17-year-old pregnant female who presented from out-of-state with severe lower urinary tract obstruction (LUTO) with associated anhydramnios, focusing on the ethical questions that this case raised.

Neonates Hospitalized with Community-Acquired SARS-CoV-2 in a Colorado Neonatal Intensive Care Unit.

IMPORTANCE: The novel coronavirus 2019 (SARS-CoV-2) has been well described in adults. Further, the impact on older children and during the perinatal time is becoming better studied. As community spread increases, it is important to recognize that neonates are vulnerable to community spread as well. The impact that community-acquired SARS-CoV-2 has in the neonatal time period is unclear, as this population has unique immunity considerations. OBJECTIVE: To report on a case series of SARS-CoV-2 in neonates through community acquisition in the USA. DESIGN: This is an early retrospective study of patients admitted to the Neonatal Intensive Care Unit (NICU) identified as having SAR-CoV-2 through positive real-time polymerase chain reaction assay of nasopharyngeal swabs. FINDINGS: Three patients who required admission to the NICU between the ages of 17 and 33 days old were identified. All 3 had ill contacts in the home or had been to the pediatrician and presented with mild to moderate symptoms including fever, rhinorrhea, and hypoxia, requiring supplemental oxygen during their hospital stay. One patient was admitted with neutropenia, and the other 2 patients became neutropenic during hospitalization. None of the patients had meningitis or multiorgan failure. CONCLUSIONS AND RELEVANCE: Infants with community-acquired SARS-CoV-2 may require hospitalization due to rule-out sepsis guidelines if found to have fever and/or hypoxia. Caregivers of neonates should exercise recommended guidelines before contact with neonates to limit community spread of SARS-CoV-2 to this potentially vulnerable population, including isolation, particularly as asymptomatic cases become prevalent.

Testosterone Treatment in Infants With 47,XXY: Effects on Body Composition.

CONTEXT: Boys with XXY have greater adiposity and a higher risk of cardiovascular disease. Infants with XXY have lower testosterone concentrations than typical boys, but no studies have evaluated adiposity in infants with XXY or the physiologic effects of giving testosterone replacement. OBJECTIVE: To determine the effect of testosterone on body composition in infants with XXY. DESIGN: Prospective, randomized trial. SETTING: Tertiary care pediatric referral center. PARTICIPANTS: 20 infants 6 to 15 weeks of age with 47,XXY. INTERVENTION: Testosterone cypionate 25 mg intramuscularly monthly for three doses vs no treatment. MAIN OUTCOME MEASURES: Difference in change in adiposity (percent fat mass z scores); other body composition measures, penile length, and safety outcomes between treated and untreated infants; and comparison with typical infants. RESULTS: The increase in percent fat mass (%FM) z scores was greater in the untreated group than in the treated group (+0.92 ± 0.62 vs -0.12 ± 0.65, P = 0.004). Increases in secondary outcomes were greater in the testosterone-treated group for total mass, fat-free mass, length z score, stretched penile length, and growth velocity (P < 0.002 for all). At 5 months of age, adiposity in untreated infants with XXY was 26.7% compared with 23.2% in healthy male infants of the same age (P = 0.0037); there was no difference in %FM between the treated XXY boys and controls. Reported side effects were minimal and self-limited; no serious adverse events occurred. CONCLUSIONS: Adiposity of untreated infants was 15% greater than that of male controls by 5 months of age. Testosterone treatment for infants with XXY resulted in positive changes in body composition.

Can Fetal Limb Soft Tissue Measurements in the Third Trimester Predict Neonatal Adiposity?

OBJECTIVES: Neonatal adiposity is associated with chronic metabolic sequelae such as diabetes and obesity. Identifying fetuses at risk for excess neonatal body fat may lead to research aimed at limiting nutritional excess in the prenatal period. We sought to determine whether fetal arm and leg soft tissue measurements at 28 weeks' gestation were predictive of neonatal percent body fat METHODS : In this prospective observational cohort study of singleton term pregnancies, we performed sonography at 28 and 36 weeks' gestation, including soft tissue measurements of the fetal arm and thigh (fractional limb volume and cross-sectional area). We estimated the neonatal body composition (percent body fat) using anthropometric measurements and air displacement plethysmography. We estimated Spearman correlations between sonographic findings and percent body fat and performed modeling to predict neonatal percent body fat using maternal characteristics and sonographic findings. RESULTS: Our analysis of 44 women yielded a mean maternal age of 30 years, body mass index of 26 kg/m(2), and birth weight of 3382 g. Mean neonatal percent body fat was 8.1% by skin folds at birth and 12.2% by air displacement plethysmography 2 weeks after birth. Fractional thigh volume measurements at 28 weeks yielded the most accurate model for predicting neonatal percent body fat (R(2) = 0.697; P = .001), outperforming models that used abdominal circumference (R(2)= 0.516) and estimated fetal weight (R(2)= 0.489). CONCLUSIONS: Soft tissue measurements of the fetal thigh at 28 weeks correlated better with neonatal percent body fat than currently used sonographic measurements. After validation in a larger cohort, our models may be useful for prenatal intervention strategies aimed at the prevention of excess fetal fat accretion and, potentially, optimization of long-term metabolic health.

Women With Gestational Diabetes Mellitus Randomized to a Higher-Complex Carbohydrate/Low-Fat Diet Manifest Lower Adipose Tissue Insulin Resistance, Inflammation, Glucose, and Free Fatty Acids: A Pilot Study.

OBJECTIVE: Diet therapy in gestational diabetes mellitus (GDM) has focused on carbohydrate restriction but is poorly substantiated. In this pilot randomized clinical trial, we challenged the conventional low-carbohydrate/higher-fat (LC/CONV) diet, hypothesizing that a higher-complex carbohydrate/lower-fat (CHOICE) diet would improve maternal insulin resistance (IR), adipose tissue (AT) lipolysis, and infant adiposity. RESEARCH DESIGN AND METHODS: At 31 weeks, 12 diet-controlled overweight/obese women with GDM were randomized to an isocaloric LC/CONV (40% carbohydrate/45% fat/15% protein; n = 6) or CHOICE (60%/25%/15%; n = 6) diet. All meals were provided. AT was biopsied at 37 weeks. RESULTS: After ∼7 weeks, fasting glucose (P = 0.03) and free fatty acids (P = 0.06) decreased on CHOICE, whereas fasting glucose increased on LC/CONV (P = 0.03). Insulin suppression of AT lipolysis was improved on CHOICE versus LC/CONV (56 vs. 31%, P = 0.005), consistent with improved IR. AT expression of multiple proinflammatory genes was lower on CHOICE (P < 0.01). Infant adiposity trended lower with CHOICE (10.1 ± 1.4 vs. 12.6 ± 2%, respectively). CONCLUSIONS: A CHOICE diet may improve maternal IR and infant adiposity, challenging recommendations for a LC/CONV diet.

Exposure to prenatal smoking and early-life body composition: the healthy start study.

OBJECTIVES: To examine associations between exposure to prenatal smoking and early-life changes in fat mass (FM), fat-free mass (FFM), and anthropometrics. METHODS: About 670 mother-offspring pairs were analyzed in the longitudinal Healthy Start study. Maternal smoking data were collected during prenatal research visits. Offspring body composition and size were measured by air displacement plethysmography at delivery and postnatal follow-up (5 months) visits. RESULTS: Comparing exposed and unexposed offspring, exposure to prenatal smoking was significantly associated with reduced neonatal FM (P = 0.007) and FFM (P = 0.02). In contrast, at 5 months, exposed offspring had comparable FM (P = 0.61) and FFM (P = 0.41). After subsequent adjustment for birth weight, offspring exposed to prenatal smoking had significantly greater FFM (154.7 g, 0.5, 309.0; P = 0.049) and sum of skinfolds (2.7 mm, 0.06, 5.3; P = 0.04). From delivery to follow-up, exposed offspring had significantly greater increases in FFM (156.4 g, 2.8, 310.1; P = 0.046) and sum of skinfolds (2.7 mm, 0.06, 5.3; P = 0.04), even after adjustment for respective delivery measures. CONCLUSIONS: Exposure to prenatal smoking was significantly associated with rapid postnatal growth, which may increase the offspring's risk of metabolic diseases.

Quantity and timing of maternal prenatal smoking on neonatal body composition: the Healthy Start study.

OBJECTIVE: To examine the dose-dependent and time-specific relationships of prenatal smoking with neonatal body mass, fat mass (FM), fat-free mass (FFM), and FM-to-FFM ratio, as measured by air-displacement plethysmography (PEA POD system). STUDY DESIGN: We analyzed 916 mother-neonate pairs participating in the longitudinal prebirth cohort Healthy Start study. Maternal prenatal smoking information was collected in early, middle, and late pregnancy by self-report. Neonatal body composition was measured with the PEA POD system after delivery. Multiple general linear regression models were adjusted for maternal and neonatal characteristics. RESULTS: Each additional pack of cigarettes smoked during pregnancy was associated with significant decreases in neonatal body mass (adjusted mean difference, -2.8 g; 95% CI, -3.9 to -1.8 g; P < .001), FM (-0.7 g; 95% CI, -1.1 to -0.3 g; P < .001), and FFM (-2.1 g; 95% CI, -2.9 to -1.3 g; P < .001). Neonates exposed to prenatal smoking throughout pregnancy had significantly lower body mass (P < .001), FM (P < .001), and FFM (P < .001) compared with those not exposed to smoking. However, neonates of mothers who smoked only before late pregnancy had no significant differences in body mass (P = .47), FM (P = .43), or FFM (P = .59) compared with unexposed offspring. CONCLUSION: Exposure to prenatal smoking leads to systematic growth restriction. Smoking cessation before late pregnancy may reduce the consequences of exposure to prenatal smoking on body composition. Follow-up of this cohort is needed to determine the influence of catch-up growth on early-life body composition and the risk of childhood obesity.

Physical activity in pregnancy and neonatal body composition: the Healthy Start study.

OBJECTIVE: To examine associations between pregnancy physical activity and neonatal fat mass and fat-free mass, birth weight, and small for gestational age (SGA). METHODS: We analyzed 826 mother-neonate pairs (term births) participating in the longitudinal Healthy Start study. The Pregnancy Physical Activity Questionnaire was used to assess total energy expenditure and meeting American College of Obstetricians and Gynecologists (College) guidelines for physical activity during early pregnancy, midpregnancy, and late pregnancy. Models were adjusted for maternal and neonatal characteristics. RESULTS: Neonates had mean fat mass of 292.9 g, fat-free mass of 2,849.8 g, and birth weight of 3,290.7 g. We observed 107 (12.9%) SGA and 30 (3.6%) large-for-gestational age neonates. A significant inverse linear trend between total energy expenditure during late pregnancy and neonatal fat mass (Ptrend=.04) was detected. Neonates of mothers in the highest compared with the lowest quartile of total energy expenditure during late pregnancy had 41.1 g less fat mass (249.4 compared with 290.5 g; P=.03). No significant trend was found with total energy expenditure and neonatal fat-free mass or birth weight. Early-pregnancy and midpregnancy total energy expenditure were not associated with neonatal outcomes. No significant trend was observed between late-pregnancy total energy expenditure and SGA (Ptrend=.07), but neonates of mothers in the highest compared with the lowest quartile had a 3.0 (95% confidence interval 1.4-6.7) higher likelihood of SGA. Meeting the College's physical activity guidelines during pregnancy was not associated with differences in neonatal outcomes. CONCLUSION: Increasing levels of late-pregnancy total energy expenditure are associated with decreased neonatal adiposity without significantly reduced neonatal fat-free mass. LEVEL OF EVIDENCE: II.

Achieving positive protein balance in the immediate postoperative period in neonates undergoing abdominal surgery.

OBJECTIVES: To determine whether neonates undergoing major abdominal surgical procedures in the first day of life could achieve a positive protein balance without protein toxicity in the immediate perioperative period by using parenteral amino acids and fentanyl analgesia. STUDY DESIGN: Newborns undergoing major surgery for gastroschisis in the first 24 hours of life (n = 13) were alternately allocated to immediate postoperative parenteral administration of 1.5 g/kg(-1)/day(-1) versus 2.5 g/kg(-1)/day(-1) amino acids. Protein balance was determined at 1.6 to 2.6 days postoperatively with both nitrogen balance and leucine stable isotope methodology. Statistical analyses were conducted with the unpaired t test and linear regression. RESULTS: Protein balance was significantly different in the 2 groups with both nitrogen balance and leucine stable isotope methodology. There was no evidence of protein toxicity as determined with blood urea nitrogen, creatinine, and ammonia concentrations. CONCLUSIONS: Neonates undergoing the metabolic stress of abdominal surgery shortly after birth are able to achieve a net positive protein balance with parenteral amino acid administration without evidence of protein intolerance.

Special circumstances: trophic feeds, necrotizing enterocolitis and bronchopulmonary dysplasia.

There are many unresolved issues regarding how to feed the extremely-low-birth-weight (ELBW) infant. Trophic feedings of small volumes of breast milk or formula do not appear to increase the incidence of necrotizing enterocolitis (NEC). For prevention of NEC, breast milk, antenatal steroids and fluid restriction each confers a benefit. Because the incidence of NEC is relatively low, to determine if a particular prevention strategy is effective, large numbers of infants would need to be enrolled in a prospective, randomized controlled trial, and such trials are rare. Candidate therapies for NEC prevention that warrant further study include oral immunoglobulins, probiotics, long-chain polyunsaturated fatty acids and arginine. Suboptimal nutrition in ELBW infants is common in the early postnatal period. This is also the most critical time for the development of bronchopulmonary dysplasia, when even brief periods of malnutrition have significant effects on lung development and growth.

Predictors of glyburide failure in the treatment of gestational diabetes.

OBJECTIVE: Our objective was to identify among women with gestational diabetes mellitus (GDM) the patient characteristics that predict treatment failure with glyburide. METHODS: Historical cohort of 95 GDM women offered glyburide after dietary failure with defined entry criteria. RESULTS: From November 2000 to May 2005, 118 women had 124 pregnancies and were offered glyburide therapy by the 2 codirectors of our Diabetes Clinic. All but 2 women elected glyburide, and 27 pregnancies were excluded due to criteria defined a priori to the study. A cohort of 95 women with 95 pregnancies were included for analysis. Nineteen percent failed glyburide. Significant predictors of failure were maternal age (34 years compared with 29 years, P = .001), earlier diagnosis of GDM (23 weeks compared with 28 weeks, P = .002), higher gravidity (P = .01) and parity (P = .03), and a higher mean fasting blood glucose (112 compared with 100 mg/dL; P = .045) compared with those successfully treated. After adjustment in the multivariable logistic regression analysis, GDM women diagnosed at a gestational age less than 25 weeks were 8.3 times more likely to fail glyburide compared with those diagnosed after 25 weeks. Maternal and fetal outcomes were favorable with a cesarean delivery rate of 25% and macrosomia rate of 7%. CONCLUSION: Glyburide was more likely to fail in women diagnosed earlier in pregnancy, of older age and multiparity, and with higher fasting glucoses, suggesting that earlier glucose intolerance and a reduced capacity to respond to an insulin secretagogue may distinguish this group. The time for glyburide as an alternative treatment has come; however, it should be prescribed after careful consideration of these patient characteristics to minimize the likelihood of failure. LEVEL OF EVIDENCE: II-2.