Clinical factors during pregnancy related to congenital cytomegalovirus infection

A group led by researchers from Kobe University has illuminated clinical factors that are related to the occurrence of congenital cytomegalovirus (CMV) infection in newborns. They revealed for the first time in the world that fever or cold-like symptoms (including cough, sore throat and runny nose) during pregnancy, and threatened miscarriage or threatened premature labor in the second trimester (14-27 gestational weeks) were associated with CMV infection in newborns.

The cross-institutional research group consisted of Kobe University Graduate School of Medicine’s Professor YAMADA Hideto (Department of Obstetrics and Gynecology), Nihon University School of Medicine’s Professor MORIOKA Ichiro (Department of Pediatrics and Child Health) and Director MINEMATSU Toshio (of Aisenkai Nichinan Hospital’s Research Center for Disease Control), among others.

Recent research conducted by this team and others has indicated that the blood tests currently carried out on pregnant women might not be effective in determining the likelihood of congenital CMV infection in newborns. This research has illuminated clinical factors during pregnancy that could be used to predict the occurrence of congenital CMV infection without relying on blood tests. This would allow at-risk newborns to be comprehensively tested and treated immediately when necessary; hopefully reducing the number of children suffering from the aftereffects of congenital CMV infection.

The results of this research were published in the American scientific journal Clinical Infectious Diseases on January 14, 2020.

Research has focused on CMV because it can cause severe aftereffects if it infects the fetus, including issues with mental and physical development and hearing loss. It is a big issue worldwide; for example, it is estimated that around 1000 babies are born with congenital CMV infections every year in Japan.

Presently there are no effective vaccines or treatments available, therefore screening all pregnant women for CMV has been discouraged. However, it has recently been revealed that prompt treatment of affected newborns with antiviral drugs can improve mental and hearing outcomes. Consequently, the importance of accurate detection of congenital CMV infections in infants prior to birth has been reasserted.

Until recently, it was thought that newborns with congenital CMV infection were born to mothers who initially acquired the infection during pregnancy (primary infection). For this reason, maternal serological screening, such as blood tests for CMV-specific immunoglobin (Ig) M, IgG antibodies, and CMV IgG avidity tests, were considered effective for detecting pregnancies with a high risk of congenital CMV infection.

However in recent years, many researchers from around the world reported that there were more infected babies born to pregnant women with chronic CMV infection prior to the affected pregnancy than those born to pregnant women with primary CMV infection. In addition, the severity of the symptoms in newborns was similar regardless of when the mother was infected. This research group also published results indicating this in Clinical Infectious Diseases in 2017. These research studies illuminated the dangers of congenital CMV infection being overlooked in some cases due to the ineffectiveness of serological screening.

Ideally, universal screening for CMV-DNA in urine samples of newborns using PCR would be able to detect all cases of congenital CMV infection, however there are currently no countries that carry out CMV PCR on all newborns. As universal neonatal screening is not practical, it would be more realistic to detect babies at high risk of congenital CMV infection prior to birth and subsequently test their urine after birth.

This research study on pregnant women who gave birth at a primary maternity hospital sought to determine whether there were any clinical factors during pregnancy that were predictive of congenital CMV infection occurrence, without using serological screening.

The cohort study was carried out on 4,125 low-risk pregnant women who received consultation and gave birth at Nadeshiko Ladies Hospital (a primary maternity hospital affiliated with Kobe University) between March 2009 and November 2019.

CMV PCR tests were conducted using urine samples from all of the infants born during the research period, nine (0.2%) of which had congenital CMV infection. Among these nine, one newborn had hearing problems. In order to determine the factors that increase the likelihood of congenital CMV infection occurrence, the research group collected the following clinical data on the all pregnant women in the study:

  • Age
  • Gravity and parity
  • BMI prior to pregnancy
  • Occupation
  • Smoking history
  • Fertility treatment history
  • Presence of fever or cold-like symptoms during pregnancy
  • History of maternal and obstetric complications; including threatened miscarriages, threatened premature labor, hypertensive disorders and gestational diabetes.
  • Non-reassuring fetal status during labor
  • Whether delivery was performed by Caesarian section.
  • Gestational age at delivery

In addition, data on the newborns, including birth weight, sex, and hearing test screening results, was also compiled.

The results from pregnancies affected by CMV and unaffected pregnancies were compared through statistical analysis of the aforementioned clinical factors. It was determined that the percentage of pregnant women who had a fever or cold-like symptoms during pregnancy was higher among those who gave birth to newborns with congenital CMV infection, compared with those who did not. In addition, threatened miscarriage or threatened premature labor in the second trimester was experienced in a higher percentage of congenital CMV infection cases. Furthermore, the research group statistically proved that these clinical factors were associated with congenital CMV infection in newborns using logistical regression analysis.

Subsequently, the optimal predictive factors for congenital CMV infection occurrence were estimated. The presence of fever or cold-like symptoms during pregnancy yielded a sensitivity of 78% and a specificity of 85%. Threatened miscarriage or threatened premature labor in the second trimester had a sensitivity of 78% and a specificity of 61%. Furthermore, if a combination of these two symptoms was experienced, then the sensitivity was 100% with a specificity of 53%.

Based on these results, it is recommended that CMV PCR tests are conducted on the newborn’s urine if the mother experiences any of the above identified factors during pregnancy.

Blood tests have enabled primary infections of CMV during pregnancy to be diagnosed, yet have been unable to predict congenital CMV infection occurrence in pregnant women with chronic infections. This has resulted in numerous cases of congenital CMV infection being overlooked.

This research study was carried out to see if the occurrence of congenital CMV infection could be linked to clinical factors during pregnancy, to allow the likelihood of infection to be predicted without conducting blood tests. The results revealed that fever or cold-like symptoms during pregnancy, and threated miscarriage or threatened premature labor in the second trimester were factors linked to congenital CMV infection.

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