Low Fetal Fraction and Birth Weight in Women with Negative First-Trimester Cell-Free DNA Screening.

OBJECTIVE: To determine the association between low fetal fraction and birth weight among women with a negative cell-free DNA (cfDNA) result for common aneuploidies in the first trimester. STUDY DESIGN: This is a retrospective cohort of women who delivered a singleton between July 2016 and June 2018 at a single institution and had normal cfDNA testing in the first trimester. The primary variable of interest was "low fetal fraction," which was defined as fetal fractions less than 5th percentile among all fetal fractions in the cohort (fetal fraction < 5.34%). The primary outcomes were birth weight ≤ 5th and ≤ 10th percentiles. Multivariable logistic regressions assessed for the association between low fetal fraction and birth weight. RESULTS: A total of 7,478 women delivered a singleton at ≥24 weeks' gestation, of which 2,387 (32%) underwent genetic screening through cfDNA; the majority were in the first trimester (n = 2,052 [86%]). 2,035 met the inclusion criteria. Birth weight ≤ 5th percentile was significantly higher in the low fetal fraction group (6.9 vs. 3.2%; p = 0.04). A low fetal fraction was associated with higher odds of an infant with a low birth weight: adjusted odds ratio (aOR) of 2.32 (95% CI 1.15-4.67) for birth weight ≤ 10th percentile (p = 0.02) and aOR of 3.73 (95% CI 1.40-9.03) for birth weight ≤ 5th percentile (p = 0.004). CONCLUSION: Low fetal fractions of ≤ 5th percentile were associated with an increased risk of birth weights ≤ 5th and ≤ 10th percentiles in women with negative cfDNA screening in the first trimester. Future work is needed to further investigate this relationship and to determine the potential clinical implications, such as third-trimester screening for growth restriction in women with low fetal fractions and negative cfDNA screening results.

De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

Understanding healthy pregnancies: the perspective of Inuit midwives in northwestern Quebec.

INTRODUCTION: For 25 years, Inuit midwives have provided perinatal and newborn care for about 90% of the pregnancies in northwestern Quebec. Patients in this region continue to have high rates of preventable nutritional deficiencies. The objective of this study was to explore the perceptions of professional midwives and students about what makes a healthy pregnancy and a healthy newborn. METHODS: We convened, via teleconference, a semistructured focus group with the local midwives and students. The conversation focused on local understanding of a healthy pregnancy and a healthy newborn, and the role of midwives in the communities. RESULTS: Four midwives and 6 students took part in the focus group, representing 80% of local midwives and students. All of the participants were women, and their professional experience ranged from 3 to 25 years. Through inductive thematic analysis, it became apparent that personal experiences and professional training were important determinants of opinions. Midwives believed that the health of women and infants could be improved through better food selection, particularly reliance on traditional nutrient-rich food. They were aware that iron deficiency was a problem and that infants required vitamin D; however, they reported that supplement uptake was poor. CONCLUSION: Concern was expressed about a decline in traditional beliefs and about unhealthy behaviours. Participants advanced strategies to promote knowledge locally (e.g., visual aids, local radio) to attempt to reduce rates of nutritional deficiencies.

INTRODUCTION: Pendant 25 ans, les sages-femmes inuites ont prodigué les soins périnataux et néonataux requis pour environ 90 % des grossesses dans le Nord-Ouest du Québec. Les patientes de cette région continuent de présenter des taux élevés de carences nutritionnelles évitables. L'objectif de cette étude était d'explorer les perceptions des sages-femmes professionnelles et des étudiantes sur ce qu'elles considèrent comme une grossesse saine et un nouveau-né en bonne santé. MÉTHODES: Nous avons organisé un groupe de discussion semi-structuré par téléconférence avec des sages-femmes et des étudiantes locales. L'entrevue a porté sur leur conception d'une grossesse saine et d'un nouveau-né en bonne santé et sur le rôle des sages-femmes dans les communautés. RÉSULTATS: Quatre sages-femmes et 6 étudiantes ont participé au groupe de discussion, représentant 80 % des sages-femmes et étudiantes locales. Toutes les participantes étaient des femmes et leur expérience professionnelle variait de 3 à 25 ans. Une analyse thématique inductive a fait ressortir que les expériences personnelles et la formation professionnelle étaient d'importants déterminants des opinions formulées. Les sages-femmes se sont dites d'avis que la santé des femmes et des nouveau-nés pouvait être améliorée par de meilleurs choix alimentaires, particulièrement en ce qui concerne l'alimentation traditionnelle, riche en éléments nutritifs. Elles étaient conscientes du fait qu'une carence en fer constitue un problème et que les nourrissons ont besoin de vitamine D. Elles ont toutefois mentionné que dans les faits, les suppléments sont peu utilisés. CONCLUSION: Les participantes ont exprimé leur inquiétude face au déclin des connaissances traditionnelles et face aux comportements malsains. Elles ont proposé des stratégies pour promouvoir la transmission des connaissances à l'échelle locale (p. ex., aides visuelles, radio locale) pour tenter de remédier aux carences nutritionnelles.

Cantú syndrome: report of nine new cases and expansion of the clinical phenotype.

Cantú syndrome, a rare disorder of congenital hypertrichosis, characteristic facial anomalies, cardiomegaly, and osteochondrodysplasia was first described in 1982 by Cantú. Twenty-three cases of Cantú syndrome have been reported to date. The pathogenesis of this rare autosomal dominant condition is unknown. We describe 10 patients with Cantú syndrome (9 new cases and the long-term follow-up of a 10th case reported by Robertson in 1999) comparing the phenotype with that of the previously reported cases. We describe how the distinctive facial appearance evolves with time and report several new findings including recurrent infections with low immunoglobulin levels and gastric bleeding in some of our patients. The cardiac manifestations include patent ductus arteriosus, septal hypertrophy, pulmonary hypertension, and pericardial effusions. They may follow a benign course, but of the 10 cases we report, 4 patients required surgical closure of the patent ductus arteriosus and 1 patient a pericardectomy. Long-term follow-up of these patients has shown reassuring neuro-developmental outcome and the emergence of a behavior phenotype including obsessive traits and anxiety.

COMT and anxiety and cognition in children with chromosome 22q11.2 deletion syndrome.

The COMT gene is thought to contribute to the cognitive/psychiatric phenotypes in 22q11.2 deletion syndrome. We measured these manifestations against the Val/Met alleles of the COMT gene, in 40 nonpsychotic 22q11DS children. The Val allele was associated with poor IQ, processing speed, executive function and a higher frequency of anxiety disorders, underscoring the importance of the COMT gene in the childhood psychopathology in 22q11DS.

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.

Predictors of gastroesophageal reflux in neonates with congenital diaphragmatic hernia.

PURPOSE: Gastroesophageal reflux (GER) is observed in 22% to 81% of neonates with congenital diaphragmatic hernia (CDH). The purpose of this study was to identify factors that may predict GER requiring fundoplication in neonates with CDH. METHODS: A retrospective chart review was performed on all neonates with CDH treated at our hospital from June 1997 to June 2005. Preoperative respiratory status, side of the CDH, and method of repair were assessed as predictors of GER and the need for fundoplication. RESULTS: Of the 42 patients with CDH, 3 died before intervention, leaving 39 patients eligible for study. All but 1 patient survived until discharge. Twenty-one (54%) developed GER of whom 9 (23%) required fundoplication. Although the side of the CDH was not a determinant of GER or the need for fundoplication, patch repair and the need for extracorporeal life support were determinants of both. CONCLUSIONS: Gastroesophageal reflux is common among babies with CDH, although symptoms often resolve without surgical intervention. Infants with CDH defects requiring a patch repair and those requiring advanced physiologic support, especially extracorporeal life support, are likely to develop severe GER necessitating fundoplication. Early recognition and treatment of GER among high-risk patients may shorten hospital stay and minimize patient morbidity. Early fundoplication should be considered for those patients at the highest risk.

Infants with congenital anomalies admitted to neonatal intensive care units.

The objective of this study was to describe the congenital anomalies in 17 Canadian neonatal intensive care units (NICUs) and their impact on mortality, morbidity, and resource utilization. This study was performed using a database analysis of 19,507 consecutive admissions. Results show that 13.7% of admissions had one or more anomalies. There was wide variation in incidence between NICUs (4.4 to 36.6%). Congenital anomalies were associated with increased severity of illness, and higher mortality, morbidity, and resource use. Inclusion of congenital anomalies improves mortality prediction in regression analyses models. Congenital anomalies have a significant impact on NICU outcomes and resource use.

Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome.

Chromosome 22q11 deletion syndrome (22q11DS) is associated with elevated rates of schizophrenia and other psychoses in adulthood. Childhood morphologic brain abnormalities are frequently reported, but the significance of these and their relationship to the development of schizophrenia are unclear. We sought to delineate midline neuroanatomical abnormalities in nonpsychotic children with 22q11DS and their age- and sex-matched controls and compare these to those reported in individuals with schizophrenia. On qualitative analysis, we found a high incidence of midline developmental abnormalities (cavum septum pellucidum, or CSP). On quantitative analysis, the total corpus callosum (CC) area was significantly increased in the patient group and among the subregions, the patients had a significantly larger isthmus. These findings of an increased area of the corpus callosum, specifically the isthmus, have not been reported before in individuals with 22q11DS. We also found a relative lack of the age-related increase in the size of the corpus callosum in the children with 22q11DS. There were no differences in cerebellar vermis measurements between the patient and control groups. Our findings are indicative of frequent midline brain anomalies, including dysgenesis of the corpus callosum, in nonpsychotic children with 22q11DS. Although the increased size of the corpus callosum in our 22q11DS patients is in direct contrast to the decrease seen in schizophrenia, the high frequency of structural midline abnormalities in these nonpsychotic children with 22q11DS is similar to that seen in schizophrenia. Further longitudinal studies on these children will help determine which of these structural abnormalities is/are pertinent to the development of psychosis.

Vasomotor instability in neonates with chromosome 22q11 deletion syndrome.

Approximately 70% of individuals with chromosome 22q11 deletion syndrome (22q11DS) have congenital heart defects. A host of other vascular problems in these patients, such as tortuous carotid arteries, Raynaud's phenomenon, unexplained hypotension, hypertension, and hypothermia, raise the possibility that there may be abnormal autonomic regulation of the vascular system. So far, however, there has been no formal report of autonomic dysfunction in patients with 22q11 deletion. We present two infants with 22q11DS, who had profound hypotension after uncomplicated surgeries for congenital heart disease. The hypotension was not responsive to vasopressor treatment (and extracorporeal membrane oxygenation in one infant) and resulted in death, due to multiorgan system failure. Obvious causes, such as poor cardiac contractility, prolonged circulatory arrest, neurological abnormality, sepsis and blood loss were excluded. On autopsy, no abnormalities were found that could explain the hypotension. We hypothesize that these infants died of severe hypotension due to abnormal vascular tone and that this is a variable feature in individuals with 22q11 deletion. The autonomic nervous system, which is responsible for the regulation of vasomotor tone, may be variably affected in 22q11DS. This could have implications for the surgical management of patients with 22q11DS. Further studies on this topic would establish or refute the association between 22q11DS and dysautonomia.

Incomplete tracheal duplication associated with severe unilateral lung hypoplasia.

A rare case of incomplete tracheal duplication with severe unilateral lung hypoplasia is presented. Photo-documentation of the gross post-mortem specimens is presented so that the anatomical aspects of this unusual anomaly can be recognized and appreciated. Clinical information is presented in the hope that successful premorbid identification of potential complications of this anomaly could be made by future physicians. To our knowledge, this is the first reported case of pathologically-confirmed duplication of the trachea.

A combination of physical examination and ECG detects the majority of hemodynamically significant heart defects in neonates with Down syndrome.

Echocardiography has become the method of choice in the diagnosis of a congenital heart defect (CHD) in neonates with Down syndrome. The most compelling argument for diagnosis of CHD in the neonatal period is the need for early surgical intervention (ideally prior to 6 months of age) in those with a complete atrioventricular (AV) canal. We evaluated the efficacy of a combined approach of physical examination (PE) and electrocardiography (ECG) in the detection of CHD in 49 neonates with Down syndrome. Our findings indicate that most hemodynamically significant defects (78%), especially a complete AV canal, can be detected by this approach. Hemodynamically insignificant minor defects, such as a small patent ductus arteriosus (PDA) and a small atrial septal defect (ASD), may be missed. Thus, echocardiography remains the most sensitive way to diagnose CHD. However, given that the combination of PE and ECG detects the majority of complete AV canal defects, it can be used as an alternative approach when echocardiography is not easily accessible, due to geographic or economic constraints. Follow-up after a few weeks of those with normal PE and ECG findings should enable detection of new symptoms and signs and evolving ECG findings that may have been missed in the immediate newborn period. Patients who are judged by PE and ECG to have CHD will need echocardiographic confirmation.