WHAT THIS EVIDENCE MEANS FOR PRACTICE
Perform predelivery amniocentesis whenever possible at the time of diagnosis of demise to obtain a cell sample for karyotype analysis to determine the cause of death.
Array-based comparative genomic hybridization makes assessment of nondividing cells possible
Raca G, Artzer A, Thorson L, et al. Array-based comparative hybridization (aCGH) in the genetic evaluation of stillbirth. Am J Med Genet A. 2009;149A:2437–2443.
Array-based comparative genomic hybridization (aCGH) makes it possible to assess the chromosome count and perform a high-resolution search for microduplications and deletions. With known segments of the genome printed on slides, the clinical scientist can analyze DNA from nondividing cells from a stillbirth. The ability to use nondividing cells is important because no cell culture is required. (Cell culture is often difficult to obtain after stillbirth.) Depending on the array selected, the resolution can be as fine as a single nucleotide polymorphism.
aCGH can inform preconception counseling
Raca and colleagues used a range of arrays to assess 15 stillbirths that involved two or more malformations. Chromosomal abnormalities, including trisomy 21 and an unbalanced translocation, were detected by aCGH in two infants. Identification of these abnormalities helped inform counseling of the parents:
- In the case of trisomy 21, parental karyotypes revealed a nontranslocation event, making it possible to assure the parents that the risk of recurrence is low
- The unbalanced translocation resulted from a balanced chromosome translocation in the mother and was associated with a significant risk of recurrence (in this case, FISH would not have helped because chromosomes 13, 18, 21, X, and Y were not involved).
Limitations of aCGH
One limitation is an inability to detect polyploidy such as triploidy or tetraploidy. This problem can be circumvented through the use of a FISH preparation prior to aCGH.
In most centers, parental blood samples are drawn at the time of aCGH studies. Because aCGH offers greater resolution of chromosome regions, an increasing number of benign variations (i.e., present in one parent) are being identified. As aCGH technology advances, we are accumulating data on copy-number variations.
A large clinical trial is needed to assess the full potential of aCGH in this setting.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Use of array-basic comparative genomic hybridization to assess cells from a stillborn fetus can help determine the cause of death and inform counseling of the parents about the risk of recurrence.
Risk factors for stillbirth include
advanced maternal age, obesity, and black race
ACOG Practice Bulletin #102: Management of stillbirth. Obstet Gynecol. 2009;113:748–760.
Willinger M, Ko CW, Reddy UM. Racial disparities in stillbirth risk across gestation in the United States. Am J Obstet Gynecol. 2009;201:469.e1–469.e8.
Fretts RC. The study of stillbirth. Am J Obstet Gynecol. 2009;201:429–430.
Women who have diseases such as insulin-dependent diabetes and systemic lupus erythematosus have long been recognized as having a six- to 20-fold increase in the risk of stillbirth, compared with the general population. However, each of these disorders accounts for 2% and less than 1% of the pregnant population, respectively, so their overall contribution to stillbirth is small. Larger portions of the population have a lower—but still significant—risk of stillbirth:
- women older than 35 years
- women who have a body mass index (BMI) above 30
- non-Hispanic black women.
Each of these categories represents 15% or more of the typical obstetric population, and each group faces a risk of stillbirth approaching 1%. The ACOG practice bulletin and the study by Willinger and colleagues address these risks in detail.
Advanced maternal age is particularly risky among nulliparous women
Advanced maternal age (>35 years) is associated with increased rates of chromosomal abnormality and maternal morbidity, such as hypertension, that are known to raise the risk of stillbirth. Even when these and other variables associated with advanced maternal age, such as placenta previa, diabetes, and multiple gestation, are controlled, however, the increased risk of stillbirth remains.
Advanced maternal age in a first pregnancy carries a particularly elevated risk. For example, the risk of stillbirth in a 40-year-old nulliparous woman is more than twice the risk in a 40-year-old multiparous woman (1 in every 116 pregnancies vs 1 in every 304).3
The increased risk of stillbirth associated with advanced maternal age is present at all gestational ages, though it becomes most profound at 37 to 42 weeks’ gestation, notably for:
- women 35 to 39 years old (1 in every 382 pregnancies; relative risk [RR] of 1.32, compared with women <35 years old; 95% confidence interval [CI], 1.22, 1.43)
- women >40 years old (1 in every 267 pregnancies; RR, 1.88; 95% CI, 1.64, 2.16).