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Concept: Congenital abnormality

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Objective To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (≥40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy.Design Population based cohort study.Setting Nationwide Swedish registries.Participants 1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages.Exposure Maternal BMI at the first prenatal visit.Main outcome measures Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year.Results A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.Conclusions Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range.

Concepts: Obesity, Relative risk, Body mass index, Congenital disorder, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality

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Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy.

Concepts: Developmental biology, Hyperthyroidism, Congenital disorder, Centers for Disease Control and Prevention, Congenital disorders, Methimazole, Congenital, Congenital abnormality

28

To evaluate the efficacy of laparoscopic pneumovesical ureter reimplantation for congenital malformation involving the vesicoureteral junction in children.

Concepts: Developmental biology, Ureter, Congenital disorder, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality, Junction, Texas

25

A full-term male foal born in a farm holidays in Maremma (Tuscany, Italy) was euthanized shortly after birth due to the presence of several malformations. The rostral maxilla and the nasal septum were deviated to the right (wry nose), and a severe cervico-thoracic scoliosis and anus atresia were evident. Necropsy revealed ileum atresia and agenesis of the right kidney. The brain showed an incomplete separation of the hemispheres of the rostral third of the forebrain and the olfactory bulbs and tracts were absent (olfactory aplasia). A diagnosis of semilobar holoprosencephaly (HPE) was achieved. This is the first case of semilobar HPE associated with other organ anomalies in horses.

Concepts: Brain, Cerebrum, Olfaction, Nose, Prosencephalon, Nasal cavity, Congenital abnormality, Holoprosencephaly

21

A recent unprecedented outbreak of Zika virus (ZIKV) in the Americas has been associated with microcephaly and other congenital malformations in infants as well as Guillain-Barre syndrome in adults. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Promising data from preclinical vaccine studies in mice and monkeys suggest that an effective vaccine will likely be possible, but important scientific challenges remain. Here we review the current state of ZIKV vaccine development. We discuss different vaccination strategies and we highlight challenges facing clinical evaluation of ZIKV vaccine candidates.

Concepts: Developmental biology, Vaccine, Vaccination, Congenital disorder, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality

18

Congenital anomalies are a leading cause of infant death and disability and their incidence varies between ethnic groups in the UK. Rates of infant death are highest in children of Pakistani origin, and congenital anomalies are the most common cause of death in children younger than 12 in this ethnic group. We investigated the incidence of congenital anomalies in a large multiethnic birth cohort to identify the causes of the excess of congenital anomalies in this community.

Concepts: United Kingdom, Ethnic group, Congenital disorder, South Asia, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality

7

Nonsense-mediated decay (NMD) is an important process that is best known for degrading transcripts that contain premature stop codons (PTCs) to mitigate their potentially harmful consequences, although its regulatory role encompasses other classes of transcripts as well. Despite the critical role of NMD at the cellular level, our knowledge about the consequences of deficiency of its components at the organismal level is largely limited to model organisms. In this study, we report two consanguineous families in which a similar pattern of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutations in SMG9, encoding an essential component of the SURF complex that generates phospho-UPF1, the single most important step in NMD. By knocking out Smg9 in mice via CRISPR/Cas9, we were able to recapitulate the major features of the SMG9-related multiple congenital anomaly syndrome we observed in humans. Surprisingly, human cells devoid of SMG9 do not appear to have reduction of PTC-containing transcripts but do display global transcriptional dysregulation. We conclude that SMG9 is required for normal human and murine development, most likely through a transcriptional regulatory role, the precise nature of which remains to be determined.

Concepts: DNA, Gene, Genetics, Gene expression, Developmental biology, Genetic code, Congenital disorder, Congenital abnormality

5

The recent emergence of Zika in Brazil and its association with increased congenital malformation rates has raised concerns over its impact on the birth rates in the country. Using data on the incidence of Zika in 20152016 and dengue in 2013 and 2015-16 for the city of Rio de Janeiro (pop: 6.4 million), we document a massive increase of Zika in women compared to men.

Concepts: Population, Congenital disorder, São Paulo, Rio de Janeiro, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality

5

IMPORTANCE Metoclopramide, a drug frequently used for nausea and vomiting in pregnancy, is thought to be safe, but information on the risk of specific malformations and fetal death is lacking. OBJECTIVE To investigate the safety of metoclopramide use in pregnancy. DESIGN, SETTING, AND PARTICIPANTS Register-based cohort study in Denmark, 1997-2011. From a cohort of 1 222 503 pregnancies, metoclopramide-exposed and unexposed women were matched (1:4 ratio) on the basis of age, calendar year, and propensity scores. MAIN OUTCOMES AND MEASURES Primary outcomes were major congenital malformations overall, 20 individual malformation categories (selected according to power criteria), spontaneous abortion, and stillbirth. In matched analyses, logistic regression was used to estimate prevalence odds ratios of malformations and Cox regression to estimate hazard ratios (HRs) of spontaneous abortion. RESULTS Among 28 486 women exposed to metoclopramide in the first trimester, 721 had an infant with a major congenital malformation (25.3 [95% CI, 23.5-27.1] cases per 1000 births), compared with 3024 among 113 698 unexposed women (26.6 [95% CI, 25.7-27.5] per 1000 births). There were no significant associations between metoclopramide use and malformations overall (prevalence odds ratio, 0.93 [95% CI, 0.86-1.02]) or any of the 20 individual malformation categories, eg, neural tube defects, transposition of great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, cleft lip, cleft palate, anorectal atresia/stenosis, and limb reduction (upper limit of 95% CI below 2.0 for 17 of 20 categories). Metoclopramide was not associated with increased risk of spontaneous abortion (757 cases [20.0 {95% CI, 18.5-21.4} per 1000] among 37 946 metoclopramide-exposed women and 9414 cases [62.1 {95% CI, 60.9-63.3} per 1000] among 151 661 unexposed women; HR, 0.35 [95% CI, 0.33-0.38]) and stillbirth (142 cases [3.5 {95% CI, 2.9-4.1} per 1000] among 40 306 metoclopramide-exposed women and 634 cases [3.9 {95% CI, 3.6-4.2} per 1000] among 161 098 unexposed women; HR, 0.90 [95% CI, 0.74-1.08]). CONCLUSIONS AND RELEVANCE Metoclopramide use in pregnancy was not associated with increased risk of major congenital malformations overall, any of the 20 individual malformation categories assessed, spontaneous abortion, or stillbirth. These safety data may help inform decision making when treatment with metoclopramide is considered in pregnancy.

Concepts: Pregnancy, Developmental biology, Abortion, Congenital disorder, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality

4

Congenital heart disease (CHD) is the most common congenital malformation and causes major morbidity and mortality. Prenatal detection improves the neonatal condition before surgery, resulting in less morbidity and mortality. In the Netherlands a national prenatal screening programme was introduced in 2007. This study evaluates the effects of this screening programme.

Concepts: Developmental biology, Netherlands, Congenital disorder, Centers for Disease Control and Prevention, Prostitution in the Netherlands, Congenital disorders, Congenital, Congenital abnormality