CMV Infection In Multiple Pregnancy – The Unpredictability Of Infectivity And Affectivity  

^*CJ McGavigan¹, V Sivaprakasam², C Aitken²,  F MacKenzie¹ 

¹Department of Obstetric and Gynaecology, Princess Royal Maternity Hospital, 16 Alexandra Parade, Glasgow G31 2ER 

² West of Scotland Specialist Virology Centre, Regional Virus Lab, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN 

^*Corresponding author email:  jmcgavigan@hotmail.com

ABSTRACT

Congenital CMV infections are the commonest congenitally transmitted infections affecting 0.5 to 2 % of all live births around the globe.¹Here we report a case of congenital CMV infection in a woman with a triplet pregnancy with variable outcomes in all three fetuses.

INTRODUCTION

Congenital CMV infections are the commonest congenitally transmitted infections affecting 0.5 to 2 % of all live births around the globe.¹ The sero-prevalence of CMV in pregnant women in Europe is 45% (43 – 73%).² Primary CMV infections in pregnancy carry a 30-40 % risk of transmission from the mother to fetus as opposed to the risk of less than 1% in reactivated CMV. Approximately 10% of infected babies are symptomatic at birth, of which 30% succumb to the infection. Most of the surviving babies manifest long-term sequelae of the central nervous system (CNS) such as hearing loss, mental retardation, seizures and chorioretinitis. Amongst those who are asymptomatic at birth, 10-15% go on to develop long-term sequelae.^3,4,5,6 Here we report a case of congenital CMV infection in a woman with a triplet pregnancy with variable outcomes in the fetuses.

CASE REPORT 

 A 34 year old para 1 booked for antenatal care at approximately 10 weeks gestation. An ultrasound scan confirmed a triplet pregnancy comprising of monochorionic twins and a dichorionic singleton. 

At 16 weeks ultrasound examination revealed the demise of one of the monochorionic twins. The two other fetuses appeared to be growing appropriately. The risks of the current situation were carefully explained to the mother – including potential of death or possible neurological damage in the surviving monochorionic twin. 

Weekly ultrasound was then carried out looking for evidence of fetal anaemia in the surviving monochorionic twin.  

At 18 weeks detailed morphology scans were performed on the two surviving fetuses– these were normal.

The antenatal course was otherwise uncomplicated and at 38 weeks the mother was admitted for induction of labour. This was performed initially with vaginal prostaglandins and then with artificial rupture of membranes and intravenous syntocinon. She progressed to full dilatation and had a spontaneous vertex delivery of the first baby (dichorionic singleton) - a female weighing 3.45kg (between the 50^th and 95^th centile for gestational age). The second baby (monochorionic surviving twin) had an assisted breech delivery.  This child was also female and weighed 2.58kg (between the 3^rd and10^th centile for gestational age). Both were born in good condition with Apgar scores of 9 and 7 at one minute and 10 (for both) at 5 minutes respectively.

Third stage of labour was confirmed complete with delivery of the placenta and fetus papyraceous.

The babies were well postnatally and both were breast fed. In view of the intrauterine death of one of the monochorionic twins, neurodevelopmental follow up was arranged. Cranial scans were performed prior to discharge. No significant abnormality was seen in the first baby however in the second twin small echogenic lesions were seen in the thalami the significance of which was unclear. A repeat scan 6 weeks later for this child was normal.

Pathological examination was carried out on the fetus papyraceous and placenta. The pathology report confirmed a fetus papyraceous of approximately 13-14 weeks size. Further anatomical detail was difficult to ascertain given the duration of death and size of the fetus.  The placentae were fused to a single mass. One cord was 23cm long and the other 47cm long. The only positive finding in the placenta was of a marked lymphohistiocytic vilitis and CMV inclusions relating to the side of the placental disc associated with the longer cord. Unfortunately there was no separate identification of the cords and thus it was not possible to conclusively say which cord belonged to which neonate.

Given this finding, maternal serum (both current and also that stored from antenatal booking blood samples) and urine, neonatal urine specimens and placental tissue were tested for CMV viral status.  The results of these tests are summarised below in Tables I, II and III.These tests revealed that the mother had seroconverted to CMV during pregnancy indicating a primary infection. On detailed questioning the mother confirmed a viral like illness during the first trimester of the pregnancy.  Tests (both laboratory and clinical) on the neonates and examination of the placenta suggest that the fetuses which shared the infected placenta developed congenital CMV resulting in the demise of one fetus whilst the other was growth restricted (in comparison to the dichorionic singleton), had possible cerebral calcification (echogenic thalamic lesions) at birth and sensorineural deafness. 

Table I: Tests on the mother

Table II: Tests on the neonates and clinical outcome 

Table III: Tests on the placenta 

Clinically, the neonates were followed up by the paediatric team. At approximately 3 months of age, twin 1 (known to be CMV negative) was thriving and audiological testing on this child was normal. Twin 2 however was found to have a profound hearing loss on the right side. On examination she looked somewhat pale and her spleen was enlarged consistent with congenital CMV infection – there was however no hepatomegaly. This child continued to excrete CMV in her urine, 8 months after birth.

DISCUSSION 

CMV is the commonest congenital viral infection in pregnancy. The virus can be isolated from 1% of all neonates. Of these, 10-15% will have symptoms at birth.⁷ The remaining 85-90% are asymptomatic but up to 15% develop delayed sequelae such as sensorineural deafness. Mortality from neonatal CMV disease is approximately 20-30% with 90% of survivors having long term sequelae.

Fetal infection occurs with primary as well as re-activated infection. Primary and early onset infection (e.g. 1^st trimester) pose a greater risk to the fetus than reactivation of the virus or infection in later pregnancy.⁷ Primary infection occurs in approximately 2% of pregnant women and is associated with a 30 to 40% risk of intrauterine transmission and clinical disease.⁷ Reactivated infection is associated with a 10 fold lower rate of viral transmission to the fetus.⁸

The differential outcome of the fetuses involved in both primary and reactivated CMV infection has been a matter of great discussion and debate.^{5, 6, 9}

Maternal factor

Stern et al. suggested that an abnormal maternal immunological response could facilitate viral transmission and subsequent fetal infection.¹⁰ This group showed that lymphocytes from the mothers of affected babies failed to respond to antigen in CMV transformation tests, whereas lymphocytes from mothers who did not transmit the virus did respond. In essence these women might not have the immunological capacity to limit viral replication.¹¹ This explanation however is not sufficient to explain why in this case all 3 fetuses (exposed to the same maternal milieu) were affected so differently. It would suggest that other factors may be involved.  

Placental and Amniotic Fluid factors

The placenta is likely to be the main portal of infection to the fetus given positive histopathologic findings in this organ in most cases of congenital CMV.¹² Interestingly however in up to 60% of cases with positive placental pathology, the fetus is not infected which would suggest that the placenta may also have a protective role.⁹ 

Fisher et al using in-vitro experiments employing first-trimester chorionic villi and isolated cytotrophoblasts, demonstrated that placental permissiveness and infection of the placenta is central to transmission of CMV infection to the fetus.¹³ They inferred that the syncitiotrophoblast which is in direct contact with the mother’s blood pass the CMV infection to the underlying cytotrophoblast. It is known that the syncitiotrophoblast express the neonatal Fc receptor hFcRn, which trancytoses maternal IgG from the maternal to fetal circulation. It is postulated that similar mechanism could enhance virion trancytosis as well, through the abundant non-neutralizing low avidity antibodies following a primary CMV infection, across the placental barrier. This might also explain the phenomenon of efficient intrauterine infection in the presence of high antibody titers to CMV.⁸

Infection with CMV has been shown to alter placental immune function by disrupting the cytotrophoblastic expression of HLA-G.¹³ This molecule is intricately involved in the pathway which protects fetal cells from being destroyed by the maternal immune system. This is particularly so during the first trimester of pregnancy. Subsequently the timing of infection would significantly determine the effect on the pregnancy outcome.

Interestingly in this case the dichorionic singleton and its placenta were not affected. Given that all three fetuses were exposed to the same maternal viral milieu it is possible that this placenta acted as a protective barrier.

Several studies have looked at viral load in amniotic fluid as a predictor of the likelihood of fetal infection. In some cases a high viral load in the amniotic fluid was able to identify fetuses at higher risk of developing a severe infection.^{6, 14, 15} However a more recent study by Lazzarotto et al. shows that twin fetuses may react differently to primary maternal infection despite being exposed to the intrauterine environment. ⁶

Fetal factor

Alfhor et al. found that in monozygotic (MZ) twins, infection regularly occurred in both members of the pair.⁵ In this study all pairs were stated as having monochorionic placentae. It was felt that by being supplied by a common placenta and equipped with identical genetic codes these fetuses probably reacted to maternal CMV infection as a unit. The findings in dizygotic (DZ) twins were less homogenous and the group concluded that DZ twins with separate placentae should be looked upon as independent individuals with different genetic codes and hence different resistance to infection.⁵

In conclusion, it is not only the maternal immunity that determines the degree to which a fetus is infected in congenital CMV but also the integrity of the placenta, which is determined by as yet, unidentified multiple factors. The knowledge that congenital CMV infections in multiple pregnancies need not affect all the fetuses could complement counselling strategies while dealing with affected mothers.

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