Research adds insight on stillbirth risk factors

Work-up and prevention

Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.

Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.

In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.

Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).

When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.

Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.

In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).

A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.

Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.

In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.

For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).

Current research

One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).