Finding a Genetic Explanation for Stillbirth

Posted by Sushrut Jangi • December 5th, 2012

Within the word “stillbirth” is almost unbearable contradiction, an image of immobility and silence when what we expect is rigorous movement, a loud and explosive cry, a rapid and hammering heartbeat, all the physical warmth of new life.  Parents who confront a stillborn child are forced to deal with the viscerality of this contradiction, requiring them to reverse profound expectations; this is an unparalleled grief.   The majority of the 3 million world-wide stillbirths per year occur almost invisibly in low-income and middle-income countries (98%) and usually result from complications during labor itself.   However, high-income countries, such as the United States, face stillbirth in 1 of every 160 births, a rate that has not improved in the past several years, and which is approximately equivalent to infant mortality.   When stillbirth occurs, parents and clinicians often look for explanations to help reach emotional closure and potentially prevent recurrence in future pregnancies.  However, what makes stillbirth even more frustrating beyond its unexpectedness is that in many cases, an explanation for the event can’t be found.  In fact, the cause of 25 to 60% of stillbirths remain unexplained.

This grail – the cause of the stillbirth – has been difficult to pursue.   A physician who encounters fetal death does have various routes of investigation to determine cause, however, the optimal evaluation remains uncertain.  The recommended components of this kind of investigation includes an exhaustive medical history, an autopsy under the guidance of an experienced perinatal pathologist, evaluation of placental pathology, and karyotype analysis.   However, in nearly 50% of stillbirths, such systematic evaluations don’t occur.  Autopsies are frequently refused.   Clinicians themselves may be hesitant to confront grieving parents.   And, in those cases that are evaluated, a substantive proportion go unexplained.

But slowly, the pieces of the stillbirth puzzle are coming together.  The Stillbirth Collaborative Research Network, developed in partnership between the National Institute of Child Health and Human Development in Maryland along with several clinical sites across the United States, has aimed to bridge gaps in our understanding of the epidemiology of stillbirths.   Their goal is to standardize the stillbirth evaluation, capture the true incidence of the condition nationally, systematize documentation and reporting of fetal deaths, and bring patients and clinicians closer to understanding why a stillbirth occurs.  Their most recent report, published in this week’s NEJM, seeks to improve our understanding of the cause of fetal death by applying new technologies to one angle of this complex problem – the genetic explanation of stillbirth.

The karyotype – the bird’s eye view of the genetic map – is abnormal in about 10% of all stillbirths.  Yet despite this observation, little is known about the genetic causes of fetal death.  Aneuploidy, or an abnormal number of chromosomes, is usually lethal in utero:  trisomy 21, 18, 13, and monosomy X have been linked to early fetal demise.  However, some stillbirths may have chromosomal abnormalities below the resolution of the karyotype.  Capturing these abnormalities requires a finer tool.  Consequently, the authors of this study tested the hypothesis that microarray analysis of single nucleotide polymorphisms (SNPs) might be able to detect not only aneuploidy, but also smaller deletions and duplications potentially linked to genes associated with stillbirth or fetal development.

Their hypothesis proves worthwhile.   The higher resolution afforded by the microarray was able to resolve an additional 24% of cases of genetic aberrancy than using karyotype alone when evaluating for stillbirth.  Aside from the higher resolution, microarray analysis improved the chances of a genetic diagnosis because, unlike karyotyping, it can be performed on non-viable tissue.  Microarray analysis not only captured more aneuploidal stillbirths, but it also sensitively detected pathogenic deletions and duplications, especially those that may lead to both congential abnormalities in addition to fetal death.

However, not all abnormal variants detected by this technology may have overt clinical utility.  Sorting out which variants are useful and which aren’t remains a challenge.  Since this technology does provide an incremental improvement in providing a genetic explanation for stillbirth, it may bring help to bring some solace to grieving parents and catalyze the pursuit of other explanations for fetal death.  And the promise that hides in the lining of this problem is that one day, such genomic technologies may be useful in capturing aberrancies in early stages of fetal life, providing clinicians an opportunity to intervene before a deleterious cascade begins.  As another report in this week’s NEJM shows, such an era may have already begun to dawn.

For more on this topic, see the related editorial, from Dr. Lorraine Dugoff at the University of Pennsylvania Perelman School of Medicine.

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