Abstract & Commentary

Frequent Detection of Cytomegalovirus in Stillbirths

By Hal B. Jenson, MD, FAAP, Dean, Western Michigan University School of Medicine, Kalamazoo, Michigan, is Associate Editor for Infectious Disease Alert.

Dr. Jenson reports no financial relationship to this field of study.

Synopsis: Cytomegalovirus (CMV) was identified in 15% of stillbirths as the most common infectious agent — by far — associated with stillbirth. CMV infection was significantly associated with fetal thrombotic vasculopathy, suggesting the mechanism of fetal demise and compelling evidence that CMV is a cause of many stillbirths.

Source: Iwasenko JM, et al. Human cytomegalovirus infection is detected frequently in stillbirths and is associated with fetal thrombotic vasculopathy. J Infect Dis 2011;203:1526-1533.

A total of 130 singleton stillbirths from a single institution in Australia, from January 2005 through December 2006, of > 20 weeks gestation with no cause of death and with available formalin-fixed, paraffin-embedded tissues were examined by multiplex PCR for 19 infectious agents, and by immunohistochemistry for human cytomegalovirus (CMV). There were no statistically significant differences found in CMV-infected vs. CMV-uninfected cases for birth weight, birth weight percentile, gestational age, or maternal parity. There was a trend among CMV-infected fetuses for either early stillbirth (< 26 weeks) or term stillbirth (> 37 weeks) (P = 0.06), and also for female sex (P = 0.06).

CMV DNA was detected in 20 of 130 (15%) fetuses. All other infectious agents were detected in 21 (16%) fetuses with the most common being Escherichia coli (4), Fusobacterium nucleatum (3), and group B Streptococcus (3). CMV was consistently seen with nuclear and cytoplasmic distribution. In the placenta, CMV was commonly localized to the chorionic villi. Immunohistochemistry was less sensitive than PCR and detected CMV in 15 of the 20 PCR-positive cases (75%), including: kidney only (4); liver only (3); placenta only (4); kidney and liver (2); and kidney, liver, and placenta (2). Approximately half (52%) of mothers with a CMV-positive (45%) or CMV-uninfected (54%) stillborn infant were primiparous.

Postmortem examinations showed fetal thrombotic vasculopathy (presence of thrombi in the fetal circulation resulting in the clustering of fibrotic villi with the absence or degeneration of fetal capillaries in contiguous villi) among CMV-infected fetuses (P = 0.010), with an odds ratio of 3.6 (95% confidence interval, 1.3-9.9). No other postmortem finding was associated with CMV infection.

Commentary

Stillbirths remain the most common adverse pregnancy outcome with rates of 3-5 stillbirths per 1,000 births in developed countries and 20-40 per 1,000 births in developing countries. The etiology of stillbirths is unknown in half of cases. In this series, CMV greatly overshadowed any other infectious pathogen and was significantly associated with fetal thrombotic vasculopathy, suggesting the mechanism of stillbirth being CMV-associated vascular fibrosis. CMV infection of fetal endothelial and vascular cells leading to thrombosis is a plausible mechanism that would lead to fetal demise.

CMV is the most frequent cause of congenital infection (1%-2% of all newborns) and resulting birth defects, the most notable being congenital hearing loss. This study indicates that CMV is also the most frequently identified infectious cause of stillbirths, which was associated with 15% of stillbirths in this series. Taken together, these findings indicate the importance of developing an approach to control CMV infection, especially among women of childbearing age, and to reduce the risk of congenital disease and the incidence of stillbirths. Ultimately, the best mechanism for control is development and universal implementation of an effective CMV vaccine.