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OBJECTIVE: To estimate the risk of stillbirth (fetal death at 20 weeks of gestation or more) associated with specific birth defects. METHODS: We identified a population-based retrospective cohort of neonates and fetuses with selected major birth defects and without known or strongly suspected chromosomal or single-gene disorders from active birth defects surveillance programs in nine states. Abstracted medical records were reviewed by clinical geneticists to confirm and classify all birth defects and birth defect patterns. We estimated risks of stillbirth specific to birth defects among pregnancies overall and among those with isolated birth defects; potential bias owing to elective termination was quantified. RESULTS: Of 19,170 eligible neonates and fetuses with birth defects, 17,224 were liveborn, 852 stillborn, and 672 electively terminated. Overall, stillbirth risks ranged from 11 per 1,000 fetuses with bladder exstrophy (95% CI 0–57) to 490 per 1,000 fetuses with limb-body-wall complex (95% CI 368–623). Among those with isolated birth defects not affecting major vital organs, elevated risks (per 1,000 fetuses) were observed for cleft lip with cleft palate (10; 95% CI 7–15), transverse limb deficiencies (26; 95% CI 16–39), longitudinal limb deficiencies (11; 95% CI 3–28), and limb defects due to amniotic bands (110; 95% CI 68–171). Quantified bias analysis suggests that failure to account for terminations may lead to up to fourfold underestimation of the observed risks of stillbirth for sacral agenesis (13/1,000; 95% CI 2–47), isolated spina bifida (24/1,000; 95% CI 17–34), and holoprosencephaly (30/1,000; 95% CI 10–68). CONCLUSION: Birth defect-specific stillbirth risk was high compared with the U.S. stillbirth risk (6/1,000 fetuses), even for isolated cases of oral clefts and limb defects; elective termination may appreciably bias some estimates. These data can inform clinical care and counseling after prenatal diagnosis.

Previous NBDPS (National Birth Defects Prevention Study) findings from 1997 to 2003 suggested that maternal antihypertensive use was associated with congenital heart defects (CHDs). We re-examined associations between specific antihypertensive medication classes and specific CHDs with additional NBDPS data from 2004 to 2011. After excluding mothers missing hypertension information or who reported pregestational diabetes mellitus, a multiple birth, or antihypertensive use but no hypertension, we compared self-reported maternal exposure data on 10 625 CHD cases and 11 137 nonmalformed controls. We calculated adjusted odds ratios [95% confidence intervals] to estimate the risk of specific CHDs associated with antihypertensive use during the month before conception through the third month of pregnancy, controlling for maternal age, race/ethnicity, body mass index, first trimester cigarette smoking, and NBDPS site. Overall, 164 (1.5%) case mothers and 102 (0.9%) control mothers reported early pregnancy antihypertensive use for their hypertension. We observed increased risk of 4 CHD phenotypes, regardless of antihypertensive medication class reported: coarctation of the aorta (2.50 [1.52–4.11]), pulmonary valve stenosis (2.19 [1.44–3.34]), perimembranous ventricular septal defect (1.90 [1.09–3.31]), and secundum atrial septal defect (1.94 [1.36–2.79]). The associations for these phenotypes were statistically significant for mothers who reported β-blocker use or renin–angiotensin system blocker use; estimates for other antihypertensive medication classes were generally based on fewer exposed cases and were less stable but remained elevated. Our results support and expand on earlier NBDPS findings that antihypertensive medication use may be associated with increased risk of specific CHDs, although we cannot completely rule out confounding by underlying disease characteristics.

Background: Previous studies describing genetics evaluation in spontaneous coronary artery dissection (SCAD) have been retrospective in nature or presented as single case reports. As part of a dedicated clinical program, we evaluated patients in cardiovascular genetics clinic to determine the role of genetically triggered vascular disease and genetic testing in SCAD. Methods and Results: Patient data were entered prospectively into the Massachusetts General Hospital SCAD registry database from July 2013 to September 2017. Clinically indicated genetic testing was conducted based on patient imaging, family history, physical examination, and patient preference. Of the 107 patients enrolled in the registry, 73 underwent cardiovascular genetics evaluation at our center (average age, 45.3±9.4 years; 85.3% female), and genetic testing was performed for 44 patients. A family history of aneurysm or dissection was not a prevalent feature in the study population, and only 1 patient had a family history of SCAD. Six patients (8.2%) had identifiable genetically triggered vascular disease: 3 with vascular Ehlers–Danlos syndrome ( COL3A1 ), 1 with Nail–patella syndrome ( LMX1B ), 1 with autosomal dominant polycystic kidney disease ( PKD1 ), and 1 with Loeys–Dietz syndrome ( SMAD3 ). None of these 6 had radiographic evidence of fibromuscular dysplasia. Conclusions: In this series, 8.2% of the SCAD patients evaluated had a molecularly identifiable disorder associated with vascular disease. The most common diagnosis was vascular Ehlers–Danlos syndrome. Patients with positive gene testing were significantly younger at the time of their first SCAD event. A low threshold for genetic testing should be considered in patients with SCAD.

We review recent understanding of the pathophysiology, molecular biology, and management of Turner syndrome.Sophisticated genetic techniques are able to detect mosaicism in one-third of individuals previously thought to have monosomy X. Prenatal detection using maternal blood should permit noninvasive detection of most fetuses with an X chromosome abnormality. Disproportionate growth with short limbs has been documented in this condition, and a target gene of short stature homeobox, connective tissue growth factor (Ctgf), has been described. Liver disease is more common in Turner syndrome than previously recognized. Most girls have gonadal failure. Spontaneous puberty and menarche is more commonly seen in girls with XX mosaicism. Low-dose estrogen replacement therapy may be given early to induce a more normal onset and tempo of puberty. Oocyte donation for assisted reproduction carries a substantial risk, particularly if the woman has known cardiac or aortic disease. Neurodevelopmental differences in Turner syndrome are beginning to be correlated with differences in brain anatomy.An increased understanding of the molecular basis for aspects of this disorder is now developing. In addition, a renewed focus on health maintenance through the life span should provide better general and targeted healthcare for these girls and women.

Background Cardiomyopathy (CM) remains one of the leading cardiac causes of death in children, although in the majority of cases, the cause is unknown. To have an impact on morbidity and mortality, attention must shift to etiology-specific treatments. The diagnostic evaluation of children with CM of genetic origin is complicated by the large number of rare genetic causes, the broad range of clinical presentations, and the array of specialized diagnostic tests and biochemical assays. Methods and Results We present a multidisciplinary diagnostic approach to pediatric CM of genetic etiology. We specify criteria for abnormal left ventricular systolic performance and structure that suggest CM based on established normal echocardiographic measurements and list other indications to consider an evaluation for CM. We provide a differential diagnosis of genetic conditions associated with CM, classified as inborn errors of metabolism, malformation syndromes, neuromuscular diseases, and familial isolated CM disorders. A diagnostic strategy is offered that is based on the clinical presentation: biochemical abnormalities, encephalopathy, dysmorphic features or multiple malformations, neuromuscular disease, apparently isolated CM, and pathological specimen findings. Adjunctive treatment measures are recommended for severely ill patients in whom a metabolic cause of CM is suspected. A protocol is provided for the evaluation of moribund patients. Conclusions In summary, we hope to assist pediatric cardiologists and other subspecialists in the evaluation of children with CM for a possible genetic cause using a presentation-based approach. This should increase the percentage of children with CM for whom a diagnosis can be established, with important implications for treatment, prognosis, and genetic counseling.

About 10% of pregnant women experience symptoms of clinical depression. Many of them receive antidepressants, particularly selective serotonin-reuptake inhibitors (SSRIs). While SSRIs are not major teratogens, recent reports cite an increased risk of birth defects in general and of congenital heart defects, craniosynostosis, and omphalocele in connection with SSRI treatment. The investigators examined associations between maternal SSRI treatment in the first trimester of pregnancy and the risk of birth defects in mothers of 9849 infants with, and 5860 without birth defects who participated in the Slone Epidemiology Center Birth Defects Study. Participants completed a standardized interview in person or by phone within 6 months after delivery. This analysis was limited to women who conceived in the years 1993 to 2004. Infants with chromosomal defects or metabolic disorders were excluded. In contrast to other reported studies, taking SSRIs was not associated with a significantly increased risk of craniosynostosis, omphalocele, or heart defects. The odds ratio (OR) for cardiac defects overall was 1.2, with a 95% confidence interval (CI) of 0.9 to 1.6. Maternal use of sertraline was significantly associated with omphalocele (OR, 5.7; 95% CI, 1.6-20.7) and septal cardiac defects (OR, 2.0; 95% CI, 1.2-4.0). Taking paroxetine carried a significantly increased risk of right ventricular outflow tract obstruction defects (OR, 3.3; 95% CI, 1.3-8.8). No increase in risk was noted when pregnant women took other SSRIs or other types of antidepressants. Maternal use of SSRIs in early gestation was not associated with an overall increase in risk of cardiac defects in this study. While individual drugs of this class may confer an increased risk of specific defects, these abnormalities are rare and the absolute risk level is small.