Managing Infections in Pregnancy

Yves Villel Marianne Leruez-Ville

Disclosures

Curr Opin Infect Dis. 2014;27(3):251-257. 

In This Article

Cytomegalovirus Infection

The burden of congenital CMV infection has been consistent in population screening studies at birth as confirmed recently with a prevalence of around four out of 1000 births.[1] The respective contributions of primary and nonprimary infections to congenital CMV are unclear, although the latter has a significant impact.[2] Moderate or severe outcomes were reported in 11% of children with congenital CMV, all by 1 year, and all impairment detected after this age was mild. Among children symptomatic at birth, 42% had sequelae versus 14% of the asymptomatic infants (P = 0.006).[1] Indeed, for all population seroprevalences, nonprimary maternal infections could be responsible for the majority of congenital CMV infections. This proportion increases with seroprevalence, ranging from 57 to 96% for seroprevalences of 30–95%.[2] However, primary maternal infections carry a greater risk of transmission and severe sequelae for the neonate than do nonprimary infections. Hearing loss caused by congenital CMV infection cannot be definitely characterized either with the level of hearing loss or its evolution over time. Treating symptomatic children with ganciclovir leads to a better prognosis during the first year of life, after which progression or fluctuation again becomes more likely, but mainly in the untreated symptomatic group. Asymptomatic children with sensorineural hearing loss are more likely to have a stable hearing status and to develop normally.[3]

Interpretation of Serologies

Worldwide, population CMV seroprevalences vary widely (range 30–95%) but have been shown to be stable over time.[2] Although nonprimary CMV infection plays a significant role in congenital CMV, only primary infections can be detected during pregnancy and the outcome, overall, is more severe. Detection of positive CMV IgM in the first trimester of pregnancy has become more frequent with the development of first-trimester screening. Its interpretation is difficult and an objective evaluation of the risk of vertical transmission at a time when women may not yet have decided on continuing with the pregnancy might be especially relevant.

Dating the infection in pregnancy is critical to a comprehensive approach to the problem and differentiating between pre- and periconceptional infection often reflects on the accuracy of dating. Transmission rates for infection that supposedly happened before conception vary from 0 up to 16.7%. This wide variation probably reflects some inaccuracy in dating, although periconceptional infections are associated with a risk of vertical transmission of between 4.6 and 45%.[4] Leruez-Ville et al.[4] studied retrospectively a cohort of 4931 women tested for CMV IgG and IgM at 11–14 weeks. IgG avidity and maternal viraemia were also tested in 201 of them who presented with positive IgM. There was no cCMV infection in the subgroup with high avidity. In women with low or intermediate avidity, foetal transmission was 23.6%. In multivariate analysis, positive CMV PCR in maternal serum, decreasing avidity index and low IgG titres were all associated with foetal transmission [odds ratio (OR), 12.38; 95% confidence interval (CI), 1.77–86.33, P = 0.011; OR, 0.16; 95% CI, 0.03–0.95, P = 0.044; OR, 0.54; 95% CI, 0.11–0.88, P = 0.028; and OR, 0.27; 95% CI, 0.29–0.84, P = 0.010, respectively]. This allows calculation of incremental risk of foetal transmission upon which informed choice can be based and could lead to a better pickup rate of foetal infection while decreasing unnecessary invasive procedures[4,5] (Fig. 1). Unlike toxoplasmosis, the risk of vertical transmission of CMV and that of the severity of congenital infection with gestational age at maternal primary infection remains an unresolved issue. Picone et al. reviewed their own series of 238 primary infections with an overall vertical transmission of 24.9% breaking into three out of 34 (8.8%) preconceptional, 15 out of 78 (19%) periconceptional, 22 out of 72 (30.6%) first trimester, 14 out of 39 (34.1%) second trimester group and six out of 15 (40%) third trimester. Only three of the infected neonates were symptomatic at birth and they were born following primary infection in the first trimester. In this same article, they searched the literature for studies focusing on the link between gestational age at primary infection and the risk of foetal transmission. They found nine publications with a wide range of transmission rates in both first and third trimesters (22–42% and 30–77%, respectively). This is probably explained by differences in patient recruitment between centres as well as by differences in ways of diagnosing maternal primary infection between studies. Regarding the link between gestational age and severity of foetal infection, they found only three previous studies reporting on this aspect with no symptomatic cases following primary maternal infection after 25 weeks of gestation; however, the total number of cases remained low and statistics do not really help. Therefore, jumping to conclusions from there is quite a long shot.[6]

Figure 1.

Prenatal management of cytomegalovirus infection. *Negative predictive value for foetal infection. Positive predictive value for foetal infection. Negative predictive value for abnormalities at birth. FBS, foetal blood sampling. Adapted from [5].

Therapeutic Pathways

The mechanisms of action of hyperimmune immunoglobulins (HIGs) are not fully understood and could reside not only in antiviral activities due to high-avidity neutralizing antibodies but also potentially in immunomodulating activities through downregulation of cytokine-mediated cellular immune responses. Apart from several case reports, there are three case–control studies on the use of HIG in CMV infection in pregnancy, two of which were published by the same group.[7–9] They suggest that hyperimmune immunoglobulins could both prevent vertical transmission and also treat symptomatic foetuses infected by CMV. The rationale for prevention of vertical transmission is stronger than that for treatment of infected foetuses. However, given the variability in transmission rates as well as in the natural history of foetal infection, these series lack homogeneous criteria of eligibility for treatment as well as critical size and remain therefore largely unconvincing.

The issue of vertical transmission and its prevention has been addressed in a double-blind randomized control trial (RCT) comparing HIG and placebo (NaCl) in 123 pregnancies with primary CMV infection at 5–26 weeks (median 13 weeks) recruited from systematic screening with serial maternal serology within 5 weeks of primary infection. Sixty-one women were randomized to hyperimmune immunoglobulins intravenously (i.v.) and 62 received the placebo every 4 weeks up until 36 weeks or amniocentesis (NCT00881517 in clinicaltrials.gov). The results have not yet been published in a peer review journal but have been presented at several international conferences. In summary, transmission rates were of 18 out of 61 (29%) and 27 out of 62 (43%) in the HIG and placebo groups, respectively (P = 0.13) out of which 13 out of 50 (26%) and seven out of 46 (15%) were symptomatic, respectively (P = 0.22). In addition, there were six deliveries before 28 weeks in the HIG group and none in the placebo group.[10]

This could close the issue of prevention with HIG; however, the trial had been sized on the basis of the benefits reported in the likely overoptimistic observational study by Nigro et al[7] and might be underpowered. Another RCT is therefore being conducted in the United States (NCT01376778 in clinicaltrials.gov).

The role of prenatal antiviral treatment is also the subject of debate and clinical studies. The strongest rationale is in the efficacy of early and prolonged neonatal treatment with ganciclovir or valganciclovir in the prevention of neurosensory impairment of symptomatic-infected neonates.[11] More recently, a study of over 4000 very low birthweight infants (VLBW) showed that infants born with congenital CMV infection compared with noninfected VLBW controls were more likely to have hearing loss at initial screening (67 vs. 9%, P < 0.0001) and at follow-up (83 vs. 2.1%, P < 0.0001). Congenital CMV was also associated with abnormal neuroimaging (72 vs. 25%, P < 0.0001) and adverse developmental motor outcomes (43 vs. 9%, P = 0.02).[12] The rationale is therefore to treat only infected foetuses in cases in which the potential risk of prolonged antiviral therapy is likely to out weigh that of the natural history of the disease, that is symptomatic foetuses on prenatal ultrasound or MRI[5] (Fig. 1). However, the choice of an antiviral drug is made difficult by the fact that the most potent anti-CMV drugs also have the worst toxicity[13] and the delivery to the foetus is either subjected to serial invasive procedures with cumulative foetal loss rates[14] or requires a high maternal dose regimen in order to ensure sufficient transplacental passage. Ganciclovir has been ruled out for these very reasons and the only substantial level of evidence to date is being gathered with valaciclovir. The choice of valaciclovir was based on its tolerance in pregnancy and its efficacy in preemptive treatment of CMV infection in immunocompromised adults.[11] This drug has been used in cases with proven CMV intrauterine infection when the foetus presents symptoms of active infection without established brain lesions on ultrasound and or MRI. A case–control study has established that viral load in the foetal blood significantly decreased following maternal oral treatment with 8 g/day for at least 5 weeks without significant side effects to the foetus or the pregnant woman, and that treatment may allow a 20% increase in the birth of asymptomatic neonates.[15] A double-blind RCT of valaciclovir against placebo has failed to complete due to lack of recruitment and relatively easy availability of valaciclovir outside the study (NCT01037712 in clinicaltrials.gov). A phase-4 trial is now being conducted in order to evaluate the biological effect of valaciclovir in symptomatic foetuses using the Richard Simon methodology as a two-stage design in which the expected sample size is minimized if the regimen has low activity subject to constraints upon the size of the type 1 and type 2 errors. To date, recruitment has been of 28 out of 47 required cases for completion (NCT01651585 in clinicaltrials.gov).

The case for intrauterine treatment of infected foetuses, and especially of symptomatic ones, has been further strengthened by the results of a recent immuno-histological study on brain tissue of severely affected foetuses. Two main factors were found to influence the neuropathologic outcome: the density of CMV-positive cells and the tropism of CMV for stem/progenitor cells. This suggests that the wide spectrum of CMV-induced brain abnormalities is caused not only by tissue destruction but also by the particular vulnerability of stem cells during early brain development even in the case of infection at a late stage of the pregnancy.[16]

A prophylactic vaccine to prevent congenital CMV infection is a priority and is expected to become available in the near future.[17] However, what would constitute an optimal protective vaccine strategy is not clear. HCMV vaccines have focused primarily on immunization of adolescent girls and women of child-bearing age, aiming at protecting women anticipating pregnancies in the near future in order to prevent congenital infection. Both CMV-naive and CMV-immune women are at risk of acquiring CMV infections during pregnancy, with subsequent transmission to the foetus; hence, a targeted vaccination of CMV-seronegative women will not solve the problem of congenital CMV infection.[18] The goal of improving protection of the foetus by 'augmenting' immunity to CMV in a woman who is already CMV-seropositive is a challenging concept for vaccine development. Cost-effectiveness of vaccination to prevent cCMV infection and its morbid consequences in infected neonates and infants has been evaluated under a wide variety of conditions and assuming adolescent girls would be the targets. Such universal vaccination would be preferable to nonvaccination but only if the vaccine efficacy was at least 61%.[19] However, the study did not account for the duration of protection conferred by the vaccine.

Subunit vaccines targeting the major envelope glycoprotein gB have demonstrated varying degrees of efficacy against CMV infection and/or disease in high-risk human populations. A randomized, placebo-controlled trial of a recombinant CMV envelope glycoprotein B (gB) vaccine showed 50% efficacy in preventing CMV acquisition of primary CMV infection on the basis of infection rates per 100 person-years when administered within a year after they had given birth.[20] Glycoprotein vaccines for congenital CMV still require optimized adjuvants. However, whether a vaccine-induced antibody response to a single viral glycoprotein target is sufficient to prevent infection of the foetus remains unanswered. Maturation of the immune response, repeated asymptomatic reactivations and declining antibody or cellular responses over time may also influence the level of immunity after primary infection.[21] Safety considerations regarding theoretical long-term risks of a CMV live-virus approach have dampened enthusiasm for the live attenuated vaccine approach.[22]

New vaccines should be tested in preclinical models of congenital infection, but CMVs are highly species-specific, precluding the evaluation of HCMV vaccines in animal models prior to clinical trials. However, the viral genome of mouse CMV (MCMV) has recently shown areas dictating species-specificity, therefore opening the real possibility of directly studying HCMV in animal models in the future. The role of immune modulation genes in rhesus monkey (rhCMV), a model closer to HCMV, in directing cell-mediated responses, could also pave the way towards new vaccine design strategies.[23]

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