The diagnosis of CMV infection in this pregnancy has been made on the basis of fetal tissue PCR positivity for CMV DNA and immunohistochemical findings of CMV inclusion bodies and placental chronic villitis. The finding of antenatal IgM anti-CMV seronegativity and postnatal IgM anti-CMV seropositivity supports this. The lack of IgG anti-CMV response despite a minimum interval of 6 weeks from delivery to postnatal sampling (the interval is likely to have been much longer) has been reported in other cases of CMV infection particularly in the immunocompromised patient.11
Gestational CMV infection has been reported in other pregnancies with raised second trimester AFP and HCG levels, some with12–13
and some without14
classic ultrasonographic features of congenital CMV, which include early onset intrauterine growth restriction (IUGR), oligohydramnios, cerebral calcifications, microcephaly, ventriculomegaly, hepatic calcifications, echogenic bowel, fetal ascites or hydrops, and pleural and pericardial infections. Raised levels of AFP and HCG have been postulated to represent ongoing placental damage or inflammation secondary to CMV infection. Indeed, unexplained raised serum markers have been linked with adverse pregnancy outcomes, including low birth weight, stillbirth and placental abruption.15
Placental damage or inflammation caused by CMV infection may lead to the development of PET.
We identified only one other case of PET associated with CMV infection in the literature review;16
however, the fetus and placenta were both hydropic in addition to the presence of maternal peripheral oedema of PET (Mirror syndrome). Other than growth restriction, the fetus in the case we have presented displayed no structural abnormalities. A further case reported the combination of CMV infection, IUGR and abnormal umbilical artery Doppler velocimetry without maternal PET.17
Interestingly, the pattern of IUGR described in this case (cerebral growth velocity relatively spared in comparison to abdominal growth velocity) suggests the presence of placental insufficiency and histological examination of the placenta revealed CMV placentitis.
Research has previously demonstrated an association between PET and chronic or latent infections, including urinary tract infection and periodontal disease,18
herpes simplex virus type 221
, adeno-associated virus 222
and Chlamydiae pneumonia
These are thought to trigger the development of PET by hyperstimulation of the innate immune system and, thus, amplify the inflammatory environment of pregnancy. The mechanism by which this occurs, the effect on trophoblast development and how these lead to the development of PET are unknown. Many of the traditional risk factors for the development of PET, including young age at conception,23
new sexual partner23
and a sexual partner who has previously fathered a pregnancy affected by PET,24
can also be interpreted as risk factors for acquiring infections particularly those spread by close contact.
Further support for the role of CMV in the pathogenesis of PET is drawn from parallels with systemic cardiovascular disease and acute organ transplant rejection. Both these conditions bear striking histological similarities with that of PET,25–26
have been linked with CMV infection27–29
and demonstrate improved clinical outcomes with antiviral treatment.30–31
Serological evidence of immunity to CMV is present in 60–85% of the general population by adulthood.19
Unlike most other viral infections, secondary or recurrent CMV infection is able to infect the fetus and placenta; the majority of gestational CMV infections occur in women with previous serological immunity to CMV and are rarely of consequence to the fetus.10
In contrast, primary infections are associated with a 40% rate of transmission to the fetus.14
CMV infection of the placenta may persist after clearance of systemic infection, such has been demonstrated in the guinea pig.31
In the absence of maternal or fetal features associated with CMV infection, CMV infection at the materno–placental interface may be a contributing factor to the placental damage and shallow trophoblast invasion recognised in PET.
This case supports the proposal that CMV (or other latent infections) may trigger development of PET in genetically and/or environmentally susceptible individuals by infecting the placenta. Our patient displayed minor risk factors for the development of PET at booking (body mass index >30, higher than average blood pressure 125/82 for the first half of pregnancy with a past history of oestrogen-induced hypertension) and was subsequently demonstrated to be heterozygous for the prothrombin gene variant G20210A (in the absence of thrombosis of the placenta), which may have rendered her vulnerable to development of PET subsequent to additional placental insults. CMV infection of the placenta appears in this case to have provided that additional placental insult. If the infective-trigger hypothesis is substantiated, treatment or prophylaxis of infection (eg, CMV) may be able to prevent significant placental damage occurring and, thus, avert the development of PET.
- PET is a common cause of maternal and neonatal morbidity worldwide. Early onset PET is less common and possibly represents a differing pathology from that of late onset PET.
- CMV and other latent infections have been linked to the pathogenesis of early onset PET and may do so by interfering with placental development and trophoblast invasion.
- Raised AFP in the absence of structural and chromosomal defects in the fetus is a predictor of poor obstetric outcome; this may represent placental damage, such as that caused by infection. Screening for infections, including CMV, in these circumstances is appropriate and evidence of infection should prompt consideration of all management options for the pregnancy.
- Information regarding infections may provide valuable information for the management of subsequent pregnancy.