REVIEW URRENT C OPINION

Managing infections in pregnancy Yves Ville a,b and Marianne Leruez-Ville b,c

Purpose of review The management of infection in pregnancy aims mainly at improving the diagnosis and prognosis of congenital infections. Over 400 publications have dealt with this issue over the last 2 years, taking advantage of progress made not only in the epidemiological knowledge of infections but also neonatal treatment and prenatal diagnosis and interventions. The focus remains largely on viral and parasitic infections, namely cytomegalovirus (CMV) and toxoplasmosis, with the appearance of influenza as part of recent and severe outbreaks. Recent findings The prevalence of CMV infection is stable. The prediction of foetal infection from primary maternal infection is becoming more accurate and therapeutic approaches are promising, including the development of a vaccine in the near future. The prevalence of toxoplasmosis is decreasing markedly in Europe weakening the effect of preventive measures and questioning the rationale for screening. In addition, the efficacy of prenatal treatment is still under scrutiny, although no appropriate randomized controlled trial (RCT) has been undertaken. Summary Accurate dating of maternal primary infection is key to prenatal management including foetal and perinatal surveillance and therapy. Heightened prenatal surveillance following influenza infection in early pregnancy is warranted by an apparent increased risk of nonchromosomal congenital malformations in large epidemiological studies, likely as an effect of maternal hyperthermia. Keywords cytomegalovirus, congenital infection, influenza, serology, toxoplasmosis, vaccine

INTRODUCTION

CYTOMEGALOVIRUS INFECTION

The infections under review in this article are maternal infections that may affect foetal development or well being. A Medline search for congenital infection and pregnancy covering from 2012 and up to March 2014 retrieved over 443 articles of which 25% deal with cytomegalovirus (CMV) infection, 25% with research on immunology of infection and vaccination and 15% with toxoplasmosis. In addition to the usual suspects, influenza has emerged as a concern in pregnancy with over 20 recent articles reporting the risk mainly in early pregnancy. We have excluded peripartum infections and their consequences with varicella, herpes simplex type II viruses, group B streptococcus and other bacteria responsible for preterm labour or preterm prelabour rupture of the membranes. The three important levels to approach foetal infections are epidemiology and interpretation of maternal serologies and therefore dating of maternal infection, prenatal diagnostic and prognostic assessment and therapeutic possibilities.

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 ¼ 0.006) [1]. Indeed, &

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Obstetrics and Fetal Medicine Department, bFETUS Research Unit and Virology Laboratory and cNecker-Enfants Malades Hospital, Paris descartes University, Paris, France Correspondence to Yves Ville, Necker-Enfants Malades Hospital, Paris Descartes University, 149 rue de Se`vres, 75015 Paris, France. E-mail: [email protected] Curr Opin Infect Dis 2014, 27:251–257 DOI:10.1097/QCO.0000000000000066

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KEY POINTS  Foetal CMV infection may follow maternal primary infection as well as nonprimary maternal infection.  The diagnosis of maternal primary infection relies on a combined use of serologies, IgG avidity and maternal viraemia by PCR in maternal serum.  No antenatal treatment of CMV infection has been validated and two treatment modalities (hyperimmune therapy and antiviral therapy) are under evaluation.  Six-month treatment course with valganciclovir improves audiologic and neurodevelopmental outcomes of symptomatic neonates.  The efficacy of prenatal treatment of toxoplasmosis remains unproven.

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 &

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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 ]. LeruezVille 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 ¼ 0.011; OR, 0.16; 95% CI, 0.03–0.95, P ¼ 0.044; OR, 0.54; 95% CI, 0.11– 0.88, P ¼ 0.028; and OR, 0.27; 95% CI, 0.29–0.84, P ¼ 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 &

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Managing infections in pregnancy Ville and Leruez-Ville

Abnormalities at foetal ultrasound

Maternal seroconversion 2 types of management

Amniocentesis CMV PCR in amniotic fluid

Negative CMV PCR = absence of foetal infection NPV* ≈100%

Amniocentesis after 20 weeks and 6 weeks after seroconversion CMV PCR in amniotic fluid

Ultrasound every 3 weeks

Positive CMV PCR = foetal infection PPV† ≈100%

In case of ultrasound abnormalities

Amniocentesis CMV PCR in amniotic fluid

Negative CMV PCR = absence of foetal infection

Positive CMV PCR = foetal infection

Negative CMV PCR = absence of foetal infection Rare cases of delayed foetal infection NPV* ≈95%

Positive CMV PCR = foetal infection PPV† ≈100%

In all cases of foetal infection: prognosis evaluation with ultrasound every 3 weeks + foetal brain MRI at 32 weeks NNPV‡ = 85% +/– FBS for foetal platelets count No antenatal treatment validated Discussion of TOP if severe prognosis

FIGURE 1. Prenatal management of cytomegalovirus infection. Negative predictive value for foetal infection. yPositive predictive value for foetal infection. zNegative predictive value for abnormalities at birth. FBS, foetal blood sampling. Adapted from [5 ]. &

help. Therefore, jumping to conclusions from there is quite a long shot [6].

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

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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 ¼ 0.13) out of which 13 out of 50 (26%) and seven out of 46 (15%) were symptomatic, respectively (P ¼ 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 ¼ 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 &&

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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. Volume 27  Number 3  June 2014

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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 speciesspecificity, 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 ]. &&

TOXOPLASMOSIS Nonimmune pregnant women may acquire toxoplasma infection, with a 10–100% risk of transmission to the baby through transplacental transmission of the parasite. Risks of transmission to the baby are higher later in pregnancy, but manifestations in the infant are less severe. However although congenital infection in early pregnancy is rare, it can lead to miscarriages, stillbirths or the birth of children with signs of central nervous system involvement, such as hydrocephalus, meningoencephalitis and retinochoroiditis. However, retinochoroiditis can appear and relapse anytime after birth. Systematic education and serological screening of pregnant women are the most reliable and currently available strategies for the prevention, diagnosis and early treatment of the infection in the offspring because toxoplasmosis in pregnant women most often goes unrecognized. One recent

monocentric study has applied homogeneous selection criteria and the same biological techniques to determine the date of maternal contamination. Probabilities of congenital infection were less than 10% for maternal infections before 12 weeks of gestation, rose to 20.0% at 19 weeks, and 52.3% and almost 70% at 28 and 39 weeks, respectively. Overall, the probability of clinical signs at 3 years was 22%, one-third being detected after the age of 1. Long-term follow-up is therefore essential in order to control a somewhat unforeseeable evolution, and the prognosis remains generally good [24]. Treatment of the infection during the first year of life has been demonstrated to significantly improve the clinical outcome.

Seroprevalence and epidemiological consequences of screening policies Incidence and prevalence of Toxoplasma infection have markedly decreased during the last 30 years, at least in Europe. This decrease may be explained by a lower exposure to the parasite by changes in food habits and by improved hygiene practices in meat production. In France, when combining data of 42 208 women in three national perinatal surveys (NPS) and choosing the age of 30 for modelling, the incidence decreased from 7.5/1000 susceptible women in 1980 to 3.5/1000 in 2000 and 2.4/1000 in 2010. The observed incidence of seroconversion during pregnancy in NPS in 2010 was estimated at 2.1/1000 susceptible pregnant women (95% CI 1.3– 3.1). The predicted incidence and prevalence for 2020 were 1.6/1000 and 27%, respectively [25]. The same trend was reported in the UK. Seroprevalence was significantly higher in non-UK born women and in heavily mixed populations with different toxoplasma prevalence and risk behaviours; individual risk assessment may be favoured and toxoplasma screening could be justified according to risk. Epidemiological surveillance of congenital toxoplasmosis needs to be improved in order to determine the true burden of the disease and to assess the effectiveness of and the need for existing prevention programmes. In Europe, only four countries report the surveillance of congenital toxoplasmosis: Italy, Denmark, France and Germany [26,27]. There is a lack of evidence regarding knowledge of risk factors for toxoplasmosis and the impact of this knowledge on prevention. A systematic review recently showed that 90% of women seem to know about the risks of infection through consumption of raw beef and unwashed salad and 80% are aware of the risk with handling of cat litter. As far as preventive behaviours were concerned, although

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90% report washing vegetables and fruits eaten raw, only 50% know that washing hands after handling raw meat helps prevent infection and only 25% report washing their hands following potential contaminant exposure. Furthermore, there is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis, although evidence from observational studies suggests it is [24,25,28].

From neonatal treatment to prenatal management There is consensus that infected infants should be treated with pyrimethamine and sulfadiazine for 6–12 months. Amniocentesis seems advisable following primary infection because the performance of real-time PCR techniques that target the 529-bp DNA fragment of Toxoplasma gondii is excellent and a negative result is associated with a low likelihood that infection has occurred. A positive PCR result means that pyrimethamine–sulfonamides treatment can be offered and ultrasound monitoring can be intensified. When severe foetal lesions are detected, termination can be contemplated. Another reason for identifying infected foetuses before birth is to enable postnatal treatment to be initiated early after birth [24]. Although spiramycin and pyrimethamine– sulfonamides are reportedly well tolerated and nonteratogenic, we still do not know whether treating infected mothers with spiramycin, pyrimethamine– sulfonamides or a combination of these antiparasitic drugs is more effective than no treatment at reducing the incidence of foetal infection. Current recommendations are based on clinical experience rather than evidence. Among 1438 pregnant women with primary infection identified as a result of screening, those treated within 3 weeks showed a weak benefit compared with treatment started after 8 or more weeks (OR 0.48, P ¼ 0.05). Among 550 infected infants identified by perinatal screening, prenatal treatment did not significantly reduce the risk of clinical symptoms in infected infants (OR for treated vs. not treated 1.11, 95% CI 0.61–2.02). Only a large randomized controlled clinical trial would provide clinicians and patients with valid evidence of the potential benefit of prenatal treatment [29]. Furthermore, treatment may save the pregnancy without preventing infection in the neonate and lead to an increase in congenital disease [30]. This, however, does not seem to be the case. In one study, there was a significant reduction in risk since 1992 when monthly screening was introduced (59.4 vs. 46.6% at 26 weeks of gestation; 256

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P ¼ 0.038) and a better outcome at 3 years of age in infected children while applying prenatal treatment both to prevent vertical transmission and to treat infected foetuses [24]. Although these fundamental questions are not subjected to any appropriately designed RCT, a randomized phase-3 trial is currently comparing the efficacy and tolerance of prenatal therapy with pyrimethamine and sulfadiazine vs. spiramycine to reduce vertical transmission of T. gondii following primary infection in pregnancy. Prenatal diagnosis with amniocentesis is offered after 18 weeks gestation and 4–6 weeks after the maternal infection (NCT01189448 in clinicaltrials.gov).

Influenza One systematic review and meta-analysis of 33 observational studies suggests that first trimester maternal exposure to influenza is associated with an increased risk of nonchromosomal congenital abnormalities [adjusted OR (AOR) 2.00, 95% CI 1.62–2.48], broadly distributed and including neural tube defects (3.33, 2.05–5.40), hydrocephalus (5.74, 1.10–30.00), congenital heart defects (1.56, 1.13–2.14), cleft lip (3.12, 2.20–4.42), gastrointestinal tract anomalies (1.72, 1.09–2.68) and limb reduction defects (2.03, 1.27–3.27). The most likely mechanism could be hyperthermia in the embryonic period. However, these pregnancies have also been exposed to influenza-related medication. Furthermore, the observational studies gathered in this review could be subject to limitations such as confounding, retrospective maternal exposure reports and nonresponse of intended participants [31 ]. &

CONCLUSION The burden of congenital infection has shifted towards their prenatal management as a result of improved diagnostic and prognostic prenatal assessment. Although toxoplasmosis remains a potentially severe infection in high-risk women, national policies should be revised according to the decrease in prevalence and the lack of evidence surrounding current prenatal management. CMV is the main cause of neurosensorial deficit due to a congenital infection, especially hearing loss. Research in prevention through vaccination and HIG as well as in prenatal treatment in order to prevent congenital infection or its complications is active and should benefit from animal models despite the species-specificity of CMV. Influenza could be an emerging cause of congenital abnormalities that should be surveyed especially in the context of severe outbreaks. Volume 27  Number 3  June 2014

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Acknowledgements None. Conflicts of interest The authors have no conflict of interest.

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Managing infections in pregnancy.

The management of infection in pregnancy aims mainly at improving the diagnosis and prognosis of congenital infections. Over 400 publications have dea...
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