Genetic innovations and our understanding of stillbirth
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REVIEW
Genetic innovations and our understanding of stillbirth Louise Wilkins‑Haug1 Received: 26 March 2019 / Accepted: 27 February 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Stillbirth after 20 weeks gestation happens in 1 in 200 pregnancies and occurs more commonly than neonatal loss and sudden infant death syndrome (SIDs) combined. The stillbirth rate is several times greater in low as opposed to high-resource countries. However, among high-resource countries, although a lower overall stillbirth rate exists, there has been little change for several decades. Molecular genetic technologies are emerging as important contributors to our understanding of stillbirth. Initially, genetic etiologies included alterations in chromosome number or structure such as aneuploidy and microduplications and deletions. More recently, next-generation sequencing analysis in two genetic conditions, Smith Lemli Optiz Syndrome (SLOs) and the channelopathy disorders (such as long QT syndrome (LQTS)) provide examples into the association of pathogenic gene variants with stillbirth. Although these specific conditions individually account for only a small number of stillbirths, investigating these disorders provides a new and innovative approach for further understanding genetic contributors to adverse pregnancy outcomes. Our knowledge of the role of genetic disease as an etiology for stillbirth is elementary. Genomic interrogation of maternal–fetal genotypes, gene–gene, and genotype–environment interaction is lacking in stillbirth research. At the DNA sequence level, further investigation of variants of unknown significance is an opportunity for exploration of biologic pathways of importance to pregnancy loss. This review concentrates on SLO as an example of a single gene disorder with a high carrier but low affected liveborn proband rate. The channelopathy disorders are included as initial examples of genetic conditions with variable presentation including an association with sudden infant death syndrome. Highlighted are the challenges when numerous genes and variants are involved, and the task of assigning pathogenicity. The advantages and limitations of genetic evaluations are presented and avenues for further research considered.
Introduction In the United States, stillbirth occurs more commonly than neonatal death and sudden infant death combined. Stillbirth is usually characterized as fetal loss over 20 weeks gestation and occurs in 1 in 160–200 pregnancies (Hoyert and Gregory 2016). Globally, the world health organization (WHO) uses the International Classification of Disease (ICD)-9 definition of greater than 28 weeks, and 500 g (Lawn et al. 2016). Whether weight or gestational age are the best measurements may be country specific (Bose et al. 2015). The Every Newborn Action Plan (ENAP) promotes a 2030 goal of worldwide stillbirth reduction to 1 in 80 livebirths.
* Louise Wilkins‑Haug [email protected] 1
Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Rep
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