BBA - Molecular Basis of Disease 1867 (2021) 166198

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BBA - Molecular Basis of Disease

journal homepage: www.elsevier.com/locate/bbadis

Pregnancy and viral infections: Mechanisms of fetal damage, diagnosis and

prevention of neonatal adverse outcomes from cytomegalovirus to
SARS-CoV-2 and Zika virus
Cinzia Auriti a, Domenico Umberto De Rose a, *, Alessandra Santisi a, Ludovica Martini a,
Fiammetta Piersigilli b, Iliana Bersani a, Maria Paola Ronchetti a, Leonardo Caforio c
a
Neonatal Intensive Care Unit, Medical and Surgical Department of Fetus, Newborn and Infant – “Bambino Gesù” Children's Hospital IRCCS, Rome, Italy
b
Department of Neonatology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
c
Fetal and Perinatal Medicine and Surgery Unit, Medical and Surgical Department of Fetus, Newborn and Infant – “Bambino Gesù” Children's Hospital IRCCS, Rome,
Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Some maternal infections, contracted before or during pregnancy, can be transmitted to the fetus, during
Cytomegalovirus gestation (congenital infection), during labor and childbirth (perinatal infection) and through breastfeeding
Herpes simplex 1-2 (postnatal infection). The agents responsible for these infections can be viruses, bacteria, protozoa, fungi. Among
Herpes virus 6
the viruses most frequently responsible for congenital infections are Cytomegalovirus (CMV), Herpes simplex
Hepatitis B
Hepatitis C
1–2, Herpes virus 6, Varicella zoster. Moreover Hepatitis B and C virus, HIV, Parvovirus B19 and non-polio
HIV Enteroviruses when contracted during pregnancy may involve the fetus or newborn at birth. Recently, new vi­
Parvovirus B19 ruses have emerged, SARS-Cov-2 and Zika virus, of which we do not yet fully know the characteristics and
Enterovirus pathogenic power when contracted during pregnancy.
Varicella Viral infections in pregnancy can damage the fetus (spontaneous abortion, fetal death, intrauterine growth
SARS-Cov-2 retardation) or the newborn (congenital anomalies, organ diseases with sequelae of different severity). Some risk
Zika factors specifically influence the incidence of transmission to the fetus: the timing of the infection in pregnancy,
Fetuses
the order of the infection, primary or reinfection or chronic, the duration of membrane rupture, type of delivery,
Neonates
socio-economic conditions and breastfeeding. Frequently infected neonates, symptomatic at birth, have worse
outcomes than asymptomatic. Many asymptomatic babies develop long term neurosensory outcomes.
The way in which the virus interacts with the maternal immune system, the maternal-fetal interface and the
placenta explain these results and also the differences that are observed from time to time in the fetal‑neonatal
outcomes of maternal infections. The maternal immune system undergoes functional adaptation during preg­
nancy, once thought as physiological immunosuppression. This adaptation, crucial for generating a balance
between maternal immunity and fetus, is necessary to promote and support the pregnancy itself and the growth
of the fetus. When this adaptation is upset by the viral infection, the balance is broken, and the infection can
spread and lead to the adverse outcomes previously described. In this review we will describe the main viral
harmful infections in pregnancy and the potential mechanisms of the damages on the fetus and newborn.

1. Introduction during labor and childbirth (perinatal infection) and through breast­
feeding (postnatal infection). The agents responsible for these infections
Some maternal infections, contracted before or during pregnancy, can be viruses, bacteria, protozoa, fungi.
can be transmitted to the fetus, during gestation (congenital infection), Among the viruses most frequently responsible for congenital

* Corresponding author at: Neonatal Intensive Care unit, Medical and Surgical Department of Fetus - Newborn - Infant, IRCCS “Bambino Gesù” Children's Hospital,
Rome, Italy.
E-mail addresses: cinzia.auriti@opbg.net (C. Auriti), derosedomenicoumberto@gmail.com (D.U. De Rose), alessandra.santisi@opbg.net (A. Santisi), ludovica.
martini@opbg.net (L. Martini), fiammetta.piersigilli@uclouvain.be (F. Piersigilli), iliana.bersani@opbg.net (I. Bersani), mariapaola.ronchetti@opbg.net
(M.P. Ronchetti), leonardo.caforio@opbg.net (L. Caforio).

https://doi.org/10.1016/j.bbadis.2021.166198
Received 3 March 2021; Received in revised form 7 May 2021; Accepted 3 June 2021
Available online 10 June 2021
0925-4439/© 2021 Elsevier B.V. This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/).
C. Auriti et al. BBA - Molecular Basis of Disease 1867 (2021) 166198

infections are Cytomegalovirus (CMV), Herpes simplex 1-2 (HSV 1-2), infection can cause reactivations in the pregnant woman, being able to
Herpes virus 6 (HHV-6), Varicella zoster virus (VZV), Rubella virus determine fetal infection [5]. In this last situation the probability of
(RuV). Moreover, Hepatitis B and C virus (HBV and HCV), Human im­ CMV transmission to the fetus is lower than in the course of the first
munodeficiency virus (HIV), Parvovirus B19 (B19V) and non-polio maternal infection. The transplacental transmission of human CMV
Enterovirus (EV) when contracted during pregnancy may involve the infection during pregnancy is about 20–70% during the primary
fetus or newborn at birth. maternal infections, whilst the risk of transmission/disease is lower as
Recently, new viruses have emerged, severe acute respiratory syn­ 1–1,5% in case of recurrent infection [6]. Transmission may occur
drome coronavirus 2 (SARS-CoV-2) and Zika virus (ZIKV), of which we throughout the whole pregnancy period, but mainly in the first trimester
do not yet fully know the characteristics and pathogenic power when [7], coming into contact with body fluids (such as saliva, urine, blood,
contracted during pregnancy. and genital secretions) from an infected individual.
In this review we will describe the main viral harmful infections in 10–15% of infected neonates become symptomatic early after birth.
pregnancy and the potential mechanisms of the damages on the fetus Symptoms of CMV infection detectable already at birth include intra­
and newborn (Fig. 1). uterine growth retardation (IUGR), purpura, jaundice, hep­
atosplenomegaly, microcephaly, hearing impairment, and
2. Search strategy and selection criteria thrombocytopenia [8]. About 40–60% of cases symptomatic at birth
subsequently develop long-term sequelae (neurological disorders, vision
We searched PubMed using the name of the considered virus (CMV, and hear loss) [2,3]. In contrast, childhood sequelae developing after an
HSV 1-2, HHV-6, VZV, RuV, HBV, HCV, HIV, B19V, EV, SARS-CoV-2 and asymptomatic early postnatal period occur in 10–15% of cases, and
ZIKV) in combination with one of the following terms: “pregnancy, ver­ mostly include progressive hearing loss [9].
tical transmission, fetus, placenta or birth defect”. We also screened
reference lists of identified studies and additional references for this 2) Mechanisms of fetal damage
review were identified by each author based on their knowledge on the
field. We selected articles published in English from January 2000 to A proper understanding of the pathogenetic mechanisms leading to
30th April 2021 that we judged to be the most relevant and pertinent. intrauterine CMV infection is auspicable to optimize the prophylactic
We focused on articles published in the last 5 years, when possible. and/or therapeutic interventions and improve the outcome of the
affected children. However, such underlying mechanisms are not
3. Cytomegalovirus completely clear yet [10]. A key issue emerged in the last years is the key
role of placental impairment in the pathogenesis of congenital CMV
1) Characteristics of the virus infection. It is known that CMV replicates in cytotrophoblasts, and that
CMV infection interferes with cytotrophoblasts differentiation and in­
Cytomegalovirus is a DNA virus belonging to the Betaherpesvirinae vasion, inhibits the proper development of new villi and leads to
subfamily of Herpesviridae family. Congenital CMV infection, more placental edema/fibrosis and impaired transport of oxygen and nutritive
frequent in cases of poor socioeconomic status [1], may have serious substances to the fetus, which may contribute to IUGR [10–15]. This
clinical consequences [2,3]. Considering the relatively high number of means that although CMV-associated fetal disorders are for sure related
CMV seronegative women of reproductive age, the risk of primary CMV to a direct infection of the fetus, such abnormal development and
infection during gestation is relevant [4]. Moreover, unlike other in­ function of the placenta may also strongly contribute to disease devel­
fectious diseases, the risk of fetal involvement from CMV infection in opment and severity [10–12]. In addition, such CMV-related impair­
pregnancy is greater in the population, as the prevalence of serological ment of placental function may in some cases lead to IUGR even if viral
positivity in women of childbearing age is high. CMV after a first transmission to the fetus does not actually occur [11].

Fig. 1. Summary of the potential injuries of viral infections during pregnancy.

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Different molecular mechanisms cooperate to CMV-related placental administration of CMV hyperimmune globulins, which show promising
damage [10,11,13]: a) an impaired development of the extracellular efficacy but have been poorly investigated [32] and are still not
matrix, with decreased expression of integrin molecules, which leads to routinely recommended [4,28]. Recently Kagan et al. have reported in
lower cell adhesion and tissue invasion ability [16–18]; b) IL-10 medi­ literature that biweekly hyperimmune immunoglobulins administration
ated impairment of matrix metalloproteinases (MMP) activity in the at a dose of 200 IU/kg, higher than those previously studied, seems to
placenta, with subsequent lower expression of HLA molecules on cyto­ significantly prevent maternal–fetal transmission up to 20 weeks'
trophoblasts [16,19]; c) activation of the peroxisome proliferator- gestation, after a primary maternal CMV infection in the first trimester
activated receptor (PPAR), interfering with the biological functions of [33].
the cytotrophoblast [20,21]. Interestingly, some of the physiopathologic The currently available antiviral drugs for CMV treatment (valaci­
mechanisms involved in CMV-related poor placentation are similar to clovir, ganciclovir and valganciclovir) have the ability to inhibit the
those detected in other pregnancy disorders based on placental insuffi­ viral DNA polymerase, although with different pharmacologic features
ciency, such as preeclampsia [22]. Considering the crucial involvement [10]. However, poor evidence also exists about the safety and efficacy
of the placental in case of CMV intrauterine infection, it is not surprising profile of antivirals for the treatment of neonatal consequences of CMV
that the timing of trophoblast infection may lead to different pregnancy [34]. A recent prospective randomized clinical trial sustains that early
outcomes, with higher incidence of fetal loss after precocious infection treatment with Valacyclovir, at a dose of 8 g per day, twice daily, re­
and of IUGR or other disorders when infection develops more tardively duces significantly CMV fetal infection after maternal primary infection
[23,24]. acquired early in pregnancy, without no adverse events [35].

3) Diagnosis of congenital infection 4. Herpes simplex viruses

Unless indicated by specific clinical conditions, such as abnormal 1) Characteristics of the virus
ultrasonographic findings (increased periventricular echogenicity, ven­
triculomegaly, intracranial calcifications and periventricular cysts), no Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are DNA vi­
laboratory testing for CMV is officially recommended during pregnancy, ruses belonging to Alphaherpesvirinae, a subfamily of the Herpesviridae
although this remains a controversial issue [25]. However, obstetricians family. Both of them, highly prevalent human pathogens, are trans­
often suggest CMV diagnostics during the first trimester of gestation. A mitted across epithelial mucosal cells and skin discontinuations, migrate
combined assessment of serological testing for CMV-specific IgM, IgG to the nerve tissues, and there are able to persist in a latent state [36].
and IgG avidity may be of help in the distinction between primary and Although the viruses have different preferential site of infection, HSV-1
secondary maternal infections [4]. However, the serological diagnosis of predominantly involving the trigeminal ganglia and HSV-2 the lumbo­
non-primary CMV infection may be challenging, since IgM might be sacral ganglia, both viruses are able to infect both the orofacial and the
poorly sensitive, detection may vary significantly and since the assess­ genital areas [36]. HSV infection is a sexually transmitted disease widely
ment of IgG titers has been poorly described [26]. Moreover, the diffused in the world [37]. Most cases of recurrent genital herpes are
detection of CMV-DNA in maternal body fluids could be reliable only if caused by HSV-2. It is estimated that in the United States of America
we have an available serological status detected before pregnancy and almost 50 million people are infected with this type of virus [37]. Since
requires molecular tests with high sensitivity and specificity to detect the highest incidence of HSV infections involves women of reproductive
viral DNA in different body fluids. When primary maternal CMV infec­ age, the risk of maternal transmission to the fetus/neonate is a major
tion is confirmed, amniocentesis with CMV polymerase chain reaction health concern [36,38–41]. The clinical condition characterized by
(PCR) performed on amniotic fluid performed after 21–22 weeks' acquisition of HSV-1 or HSV-2 without previous exposure to either virus
gestation may detect if in-utero transmission occurred [4]. Furthermore, or hence no preformed antibodies is referred to as “first-episode primary
current knowledge suggests that placental pathologic examination infection”. In contrast, the clinical condition characterized by acquisi­
might be of help in the risk assessment for CMV infection in pregnancy tion of HSV-2 in an individual with previous HSV-1 antibodies or vice
[27]. versa is referred to as “first-episode nonprimary infection”. In contrast,
After birth, a PCR assay of urine and/or saliva of the neonate should the term “reactivation” refers to the detection of HSV-1 in a patient who
also be performed within the first 3 weeks of life [28]. A universal already has HSV-1 antibodies, or of HSV-2 in a patient who already has
neonatal CMV screening using saliva or urine through PCR assay seemed HSV-2 antibodies [38,42]. Recurrence and reactivation of the infection
to be a feasible method to identity high-risk infants, even those born to are much more frequent for HSV-2 than for HSV-1 genital infection and
mothers who were not screened during pregnancy, although its cost- the prognosis and the type of counselling needed depend on the type of
effectiveness ratio is yet to be determined [29,30]. Dried blood spot genital herpes (HSV-1 or HSV-2) causing the infection. It is therefore
(DBS) samples that are routinely collected because of neonatal screening advisable that the clinical diagnosis of genital herpes is confirmed by
program for genetic and congenital disorders, could be used in order to type-specific laboratory tests and that positive subjects also be diag­
distinguish between a congenital and an acquired CMV infection [31]. nosed for HIV, considering that genital HSV infection has long been
The finding of a positive PCR on urine and/or saliva after the first 3 identified as a risk factor in HIV acquisition, with a 2- to 3-fold higher
weeks of life does not allow to distinguish with certainty the congenital risk, also due to multiple sex partners. The biological basis of increased
infection from the perinatal one. The latter, in most cases, is acquired by susceptibility is due to both increased ulceration and increased inflam­
the newborn through breastfeeding from the infected mother and usu­ mation (with higher CD4+ cells) present in the skin and mucosa of HSV-
ally has no proven sensorineural consequences. 2 infected individuals [43].

4) Prevention strategies 2) Mechanisms of fetal damage

There are currently no universal programs that offer screening for HSV infection process starts with virions binding to host cell surfaces,
pregnant women and newborns that identify infected mothers and ba­ which triggers a cascade of multiple steps leading to penetration of viral
bies early, no vaccines to prevent infection, and no conclusive evidence genome into the nucleus, release of viral DNA for replication, capsid
about optimal therapeutic strategies for CMV infection during preg­ assembly, DNA packaging, envelopment via passage through the trans-
nancy: hygiene education remains a relevant preventive strategy for Golgi network and host cell is destruction [42,44–45].
congenital CMV. Possible risk factors for HSV transmission to neonates include: a)
Possible antenatal interventions include pregnancy termination and HSV serotype (HSV1 > HSV2); b) type of maternal infection (recurrent

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HSV genital lesions are associated with lower risk for transmission to delivery and lower HSV detection by culture/PCR. The recommended
exposed neonates than primary HSV genital lesions; c) maternal seros­ regimen of therapy in pregnant women with recurrent genital herpes is
tatus; d) delivery mode (vaginal delivery > cesarean section); e) pro­ Acyclovir 400 mg orally three times a day or Valacyclovir 500 mg orally
longed duration of rupture of membranes; f) impaired fetal cutaneous twice a day, started at 36 weeks of gestation [55]. However, such
barriers (instrumentation-related) [38,39,44]. Timing of maternal intervention reduces but does not completely prevent viral transmission
infection is fundamental to establish: the risk for transmission of HSV to the neonate [55]. To date, no vaccine has proven to be effective to
infection to the neonate is high (30–50%) when women acquire genital prevent yet the acquisition of HSV-1/HSV-2 [38,39]. Strategies aimed at
HSV near the time of delivery and low (<1%) when women have pre­ preventing maternal HSV acquisition during pregnancy, such as
natal history of recurrent HSV infections or who acquire genital HSV screening of all women at 24–28 weeks of gestation with an immuno­
during the first half of pregnancy) [46]. Vertical transmission of viral globulin G-based assay and screening of all couples for HSV serology at
infection may occur during the intrauterine period (5%), in the peri­ 14–18 weeks of gestation, have been assessed in the last years but still
partum period (85.9%) or postnatally (10%) [38,39,42,44]. HSV-1 lack a final validation [38,39,56].
prevalence was higher than HSV-2 at both maternal and fetal side of
the placenta, evidencing how crossing of maternal-fetal interface is a 5. Herpes virus 6
common strategy used by HSV-1, whereas in the case of HSV-2 infection
the hematogenous route is more frequent [47]. 1) Characteristics of the virus
Intrauterine HSV infection has been associated with encephaloma­
lacia, hydrocephalus, calcifications and microcephaly [48]: HSV- Human herpesvirus 6 (HHV-6) is a double stranded DNA virus
infected neonates could display significant neurodevelopmental out­ belonging to the Betaherpesvirinae subfamily of Herpesviridae family,
comes [49]. with two distinct variants: HHV-6A and HHV-6B. In analogy with other
herpesviruses, HHV-6 can establish a latency in immune cells and is
3) Diagnosis of congenital infection capable to reactivate after the first infection [57]. Both HHV-6A and
HHV-6B replicate in immune cells (especially CD4+ T cells) but viral
From a clinical point of view, HSV congenital infection may be entry is based to different receptors: human cluster differentiation 46
associated with relevant morbidity and mortality and antiviral treat­ (CD46) is the primary receptor for HHV-6A virus, while HHV-6B uses
ment (acyclovir), with different duration according to clinical presen­ cluster differentiation 134 (CD134) [57].
tation, is desirable. Maternal HSV infection during pregnancy increase HHV-6A is sometimes isolated from immunosuppressed patients
the risk of spontaneous abortion, premature birth, and stillbirth [41]. [58], while HHV-6B infections are most frequent in early childhood and
Neonatal HSV infection may present with different clinical manifesta­ usually occur without clinical severity. Moreover HHV-6 causes pitir­
tions, predictive of both morbidity and mortality: a) skin, eyes, and iasis rosea, a self-limiting exanthematous disease that in pregnancy may
mouth herpes (SEM) disease, without involvement of the central ner­ be associated with many negative outcomes, when the infection occurs
vous system (CNS)/visceral organs, usually presenting as a vesicular before 15 weeks of gestation and the blood viral load is higher than 585
rash occurring at 10–12 days of life; b) CNS disease, with (60–70%) or copies/mL [59]. Clinical features in children vary from typical exanthem
without skin involvement, with clinical manifestations of encephalitis, subitum (also known as 6th disease) [60] to afebrile seizures [61],
potentially starting at any time within the first month of life; c) neonatal urticaria multiforme [62] and meningitis [63]. Most infants
disseminated disease, a life-threatening condition involving multiple acquire HHV-6 from the saliva of asymptomatic contacts [64].
organs including CNS, lungs, liver, adrenal, skin, eye, and/or mouth,
with about 40% of infants never developing a vesicular rash 2) Mechanisms of fetal damage
[39,42,44,50]. HSV DNA isolation in tissue culture by PCR (swabs from
conjunctivae, nasopharynx, mouth, anus; blood; cerebrospinal fluid) is a HHV-6 is known to integrate itself into human genome (chromoso­
definitive diagnostic test [39,42,44]. HSV DNA detection is also mally integrated HHV-6, ciHHV-6) at specific sites [58], through ho­
routinely performed when HSV infection is suspected [42,44]. Plasma mologous recombination between telomeric regions of human
HSV DNA levels at the time of diagnosis seem to correlate with clinical chromosomes and HHV-6 sequences [65]. The HHV-6 specific U94 gene
classification of neonatal HSV disease, being higher in infants showing product could also favor integration [65]. Congenital HHV-6 infections
disseminated HSV infection [51–52] but further validation of such occur in about 1% of neonates through two modalities: in the 86% of
findings is required. Serologic diagnosis of neonatal HSV is not usually cases the virus is integrated in maternal or paternal chromosomes and
recommended for diagnostic purposes [39]. transmitted through the germ-line; in the remaining 14% of cases
transmission occurs by transplacental route [66,67]. Furthermore,
4) Prevention strategies integration can occur in somatic cells or germinal cells, the first not
transmitting the virus via the germ line while the latter leading to half of
Currently, interventions to decrease HSV neonatal transmission gametes carry ciHHV-6 [68].
remain a challenge [38,39,53–56]. The prevention of neonatal herpes Hypothetical cellular consequences associated with ciHHV-6 include
depends on the prevention of maternal infections near delivery and on no viral gene transcription, viral gene expression and replication,
the prevention of exposure of the newborn to active maternal lesions. anomalies of telomeres and impaired chromosome stability, activation
Given the highest risk of serious neonatal infection in newborns from of cellular gene expression after integration, elimination of tissues or
women who acquire genital infection in the last trimester of pregnancy, cells expressing HHV-6 antigens by immune defense mechanisms [65].
these women must be managed by both obstetricians and infectious Exposure to viral infection during pregnancy has been associated to
diseases specialists. The history of genital herpes should be investigated preterm delivery [69] and fetal loss, as the presence of HHV-6 DNA was
in all pregnant women and at the onset of labor, all women should be detected both in the placenta of miscarrying women and in the tissues of
carefully examined for HSV 1–2 lesions. Cesarean delivery, recom­ miscarried fetuses [70]. Indeed, HHV-6A DNA can induce alterations in
mended when genital lesions or prodromal symptoms are present at the the endometrial cells and interfere with trophoblast invasion and correct
time of delivery, minimizes neonatal exposure to the virus and therefore implantation [71] and inherited ciHHV-6 has been confirmed as a risk
decreases HSV transmission, but does not completely prevent it factor for spontaneous abortion [72].
[38,39,53,55]. Antiviral suppressive therapy during pregnancy in Furthermore, persistency of viral activity in a developing brain could
women with recurrent genital herpes at 36 weeks of gestation seems to lead to poor neurodevelopmental outcomes, such as in congenital CMV
be associated with decreased occurrence of genital lesions at the time of infection and further studies are thus needed to clarify this association

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[66]. Vertical transmission of viral infection may occur during pregnancy.

The risk of contracting varicella during pregnancy is low, because
3) Diagnosis of congenital infection women of childbearing age have a high seroprevalence state. A survey
conducted in the US showed that only 5% of adults aged 20–29 years
Congenital infection is usually defined as HHV-6 DNA is detected by were susceptible to contract varicella, and only 1.1% of those aged
PCR in blood samples within 72 h since birth [58]. 30–39 years were still susceptible [77].
Transplacentally-acquired infections are those with HHV-6 DNA Maternal infection is associated with still birth and later with pre­
found in cord blood samples but with lower viral loads (≤1 genomic mature delivery. The risk of developing Congenital Varicella Syndrome
equivalent copy (gec) per 104 to 105 leukocytes, or <1 gec/μg of HHV-6 (CVS) if a pregnant woman develops varicella is 0.91%; it is low during
DNA) than in chromosomally integrated infections (≥1 gec per leuko­ the first 12 weeks (0.4%) and highest during weeks 13 to 20 (2%). On
cyte, or ≥ 1–2 × 105 gec/μg DNA) [67]. the contrary, the risk for adverse effects for the mother is greatest in the
A further method to distinguish chromosomally integrated and third trimester of pregnancy. Although rare, CVS can range in severity
transplacentally-acquired infections is to examine hair follicle samples from segmental lesions including scar and limb deformities [78] as well
for the presence of HHV-6 DNA: when congenital infection is due to as ocular abnormalities (chorioretinitis, chorioretinal scarring, cata­
ciHHV-6, HHV-6 DNA is detected in hair follicles in both the infant and racts), brain abnormalities (microcephaly, encephalitis, hydrocephaly)
at least one parent [67]. and mental retardation [79]. Children born to mothers with varicella
Infants reported by Hall and colleagues were all asymptomatic: one- during pregnancy can also develop Herpes Zoster during the first year of
third of congenital infections were due to HHV6-A, whereas in all life.
postnatal infections HHV-6B was detected [64]. The pathogenesis of CVS reflects intrauterine dissemination of
Increasing use of PCR-based pathogen detection panels in newborns infection and the failure of the fetal immune system to determine the
may lead to more always frequent diagnoses of HHV-6 and interpreta­ virus-latency, which normally occurs in postnatal VZV infection. Since
tion of this finding could be challenging to interpret [73]. VZV is a lymphotropic virus, it has the potential to spread to all fetal
organs by the hematogenous route. Examining fetuses infected with
4) Prevention strategies maternal varicella, VZV has been shown to be distributed throughout
the fetal tissues. This finding supports the hypothesis that VZV causes
Maternally acquired HHV-6 antibodies are usually found in neo­ viremia, in the absence of an adequate immune response of the fetus
nates, reflecting the high prevalence in adults [58], with a protective [80]. Given that VZV is a neurotropic virus, many of the CVS defects are
effect on their still immature immune system [74]. To date, no vaccine is the result of infection of the spinal cord and ganglia, with destruction of
available to prevent the acquisition of HHV-6. the plexus during embryogenesis and denervation of the limb bud and
Intravenous ganciclovir is feasible to decrease viral load but treat­ subsequent hypoplasia. Failure of muscle development also causes
ment for HHV-6 is appropriate only in patients who are either immu­ damage to the bone formation of the limbs. Skin lesions may reflect
nocompromised, have a high viral load (without a ciHHV-6), or present sensory nerve involvement. Infection of optic tract cells also explains
with a severe disease [73]. optic atrophy and chorioretinitis. Some skin lesions, distributed ac­
cording to dermatomers, may be caused by the reactivation of the VZV
6. Varicella zoster virus in utero. The short latency phase, if latency is established, can be
explained by the poor cell-mediated immune response in the fetus [81].
1) Characteristics of the virus Neonates born to mothers in whom varicella develops between 5 days
before delivery to 2 days after delivery have a 50% risk of developing a
The Varicella Zoster virus (VZV), also known as the human herpes “neonatal varicella”. In 23% of cases the infection can be severe or even
virus 3, is an exclusively human neurotropic virus that belongs to the life threatening, therefore these neonates must receive varicella zoster
Alpha-herpesvirinae family. Its double-stranded DNA genome (of about immunoglobulins and antiviral therapy immediately after birth. Shin­
125 kb) shares much homology with the HSV genome. The virus is gles in pregnancy is not associated with viremia and no adverse fetal
enveloped, spherical and 200 nm in diameter. It has an icosahedral sequelae have been described [82].
symmetry and the capsid consist of 162 capsomers. Glycoproteins are
embedded in the lipid envelope. VZV has no animal reservoir; its main 3) Diagnosis of congenital infection
targets are T lymphocytes, epithelial cells and ganglia. Initial infection
results in varicella (chickenpox), most commonly affecting children. The When a pregnant woman has a suspicious varicella contact, a
disease is highly infective and is characterized by a skin rash that forms serology assay should be performed to check her immune status against
small, itchy blisters that can be associated with fever. Symptoms appear varicella. In case of seronegativity, prevention should be carried out
10 to 21 days after exposure to the virus and usually last five to seven using specific immunoglobulins. Contrarywise, clinical varicella does
days. Primary infection usually confers lifelong immunity to this disease not require virology confirmation but requires immediate treatment
[75]. with immunoglobulins. Recently valacyclovir has been proposed to treat
Whereas Varicella in children is usually self-limiting, primary varicella in pregnant women [83]. If CVS is suspected invasive testing
infection in adults is usually more severe and can cause interstitial such as amniocentesis or cordocentesis can be performed to confirm
pneumonia. During the primary infection VZV becomes latent in fetal infection by detecting VZV DNA. In contrast to other viral illnesses,
ganglionic neurons and can reactivate causing Zoster (shingles), due to a VZV IgM are hard to detect in fetal blood and are not routinely tested.
decline in cell-mediated immunity. Zoster can be complicated by a wide Nevertheless, the demonstration of VZV DNA in cord blood is not syn­
range of neurologic diseases (postherpetic neuralgia, myelopathy, onymous of CVS. In fact, congenitally infected fetuses without any
retinal necrosis, vasculopathy and meningoencephalitis and cerebellitis) anatomical abnormalities have a good prognosis and no neurological
as well as visceral involvement (hepatitis and pancreatitis) [76]. impairment. Therefore, the diagnostic modality of choice to diagnose
Transmission of Varicella usually occurs through respiratory droplets CVS remains fetal ultrasound, that can detect if there are some CVS
from 48 h prior the onset of the rash until all lesions have crusted over associated abnormality [84]. When a neonate with CVS is born, it is
but can also occur through contact with the blisters and to the fetus important to determine if the disease is active. If the baby has skin le­
through placenta. sions and positive molecular or IgM serological testing for VZV, then he
should be isolated to prevent viral spread. Neonates born to mothers in
2) Mechanisms of fetal damage whom varicella developed 2 days before to 5 days after delivery should

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always be isolated because potentially infected. set of genes involved in eye and ear development has also been shown as
down-regulated in a model with RuV-infected fetal endothelial cells
4) Prevention strategies [93].
CRS includes a spectrum of several defects: eye defects (such as
Prevention strategies are crucial to prevent the risk of CVS as, cataracts, microphthalmia, chorioretinitis, corneal opacity and glau­
although rare, CVS can have serious adverse outcomes for the affected coma), sensorineural hearing loss, cardiovascular anomalies (most
child. As a live attenuated varicella vaccine is available, vaccination of commonly patent ductus arteriosus, peripheral pulmonary artery ste­
all the women in childbearing age with a negative varicella history, nosis or coarctation of aorta), brain injury (like microcephaly, hydro­
confirmed by negative VZV IgG antibody test, should be encouraged. cephalus and cerebral calcifications) [94].
Pregnancy should be avoided for at least one month after vaccination Low birth weight was observed in 9% of CRS cases [95].
[79].
If a susceptible pregnant woman is exposed to a person with vari­ 3) Diagnosis of congenital infection
cella, CDC recommends administration of varicella zoster immuno­
globulins (VariZIG) as soon as possible after exposure to varicella-zoster A confirmed case of CRS has been defined as an infant with at least
virus and within 10 days after contact [85]. one of the previously described clinical features, and a laboratory evi­
Even though varicella infection can be prevented in <50% of cases, dence of RuV by polymerase chain reaction (PCR) in a specimen at birth
immunoglobulins can reduce the severity of the disease [86]. Recently (nasopharyngeal swab, urine, cerebrospinal fluid or blood) or positive
valacyclovir has been proposed to treat pregnant women who develop RuV-specific IgM antibodies at birth to 3 months or a RuV antibody level
CMV or varicella infection early in pregnancy [35]. that persists more than expected from a passive transfer of maternal
antibodies [96]. Avidity testing of IgG could also help diagnose recent
7. Rubella virus infections.
Despite the absence of clinical signs of CRS in the second part of
1) Characteristics of the virus pregnancy where the development of most organs is already completed,
such cases are reported as Congenital Rubella Infection (CRI) if labo­
Rubella virus (RuV) is a member of the genus Rubivirus, belonging to ratory confirmed.
the family of Matonaviridae. Its genome of single-stranded RNA is Perinatal infection could be accompanied by low birthweight and
enclosed by an icosahedral capsid. The viral genome codes for the two non-specific features such as the purpuric “blue-berry muffin” rash,
non-structural (p90, p150) and three structural proteins: viral capsid hepatosplenomegaly, and thrombocytopenia [94].
protein (C) and surface glycoproteins (E1 and E2). Human beings are the A follow-up study showed that most infants with CRS later reported
only known host. Rubella infection, also known as three-day measles or sensory defects and developmental delay [97]: this explains the
German measles (because firstly described by two German physicians), importance of an early identification and an adequate follow-up.
is typically mild and occurs mostly in childhood. The exanthem for
Rubella is a maculopapular rash on the face which spreads to the trunk 4) Prevention strategies
an limbs and usually vanishes within three days, while the typical ex­
anthem (Forchheimer's sign) consists of petechiae on the soft palate: Congenital Rubella syndrome is nowadays rare in countries with a
fever, lymphadenopathy, myalgias, and arthralgias may also occur [87]. well-established immunization program against this virus and it repre­
Transmission usually occurs through respiratory droplets but can sents an important model in order to design future public health stra­
also occur to the fetus through placenta. Vertical transmission of rubella tegies against prenatal infections [96], although screening for rubella
is higher in the first weeks of gestation, leading to miscarriage, stillbirth, serostatus is still recommended for all pregnant women to promptly
or a chronic injury of several organs in the fetus, well-known as intervene and carry out the appropriate strategies in case of a positive
Congenital rubella syndrome (CRS), with the classical fetal Gregg's triad result [98]. Immunity to rubella virus is commonly determined by
of congenital cataracts, deafness, and cardiac defects [88]. measuring rubella-specific IgG, despite a lack of standardization of
available assays could influence interpretation of results [99].
2) Mechanisms of fetal damage Rubella is a vaccine-preventable viral self-limiting infection, without
a specific treatment. Live-virus vaccines, such as mumps, measles and
During maternal viremia, RuV may cross the placental barrier and rubella containing vaccine (MMR), are contraindicated during preg­
enter into the fetal circulation, causing a necrotizing vasculitis. The virus nancy and women should be advised to avoid pregnancy for one month
is probably transported as infected endothelial cell emboli, resulting in a after receiving RuV-vaccine [100]. However, there is still no evidence of
chronic injury [89]. The exact mechanisms at the basis of CRS are still CRS in infants born to mothers who had received a RuV-vaccine during
not completely understood, considering the near eradication of rubella pregnancy and an inadvertent vaccination should not be an indication
and the absence of animal models to study. for termination of pregnancy [101].
Gestational age (GA) at the time of maternal infection plays a key In case of exposure to the virus during pregnancy, polyclonal im­
role in causing fetal damage. The risk of CRS is higher during the first munoglobulins administered up to five days after seem to be of benefit
11–12 weeks of GA and then clearly decreases [90]. for preventing rubella [102].
RuV antigen was detected in several organs (lung, heart, aorta and
pulmonary artery, brain, placenta) of cases with a poor prognosis [90]. 8. Hepatitis b and C viruses
Apoptosis pathways have been showed to involve RuV-infected adult
cells, whereas apoptosis in fetal cells was not supported and this could 1) Characteristics of the virus
promote viral persistence in developing cells [91].
Furthermore, RuV infection could play an indirect role in impairing Hepatitis B virus (HBV) is a partially double-stranded DNA virus,
growth and differentiation mechanisms through secretion of interferon belonging to the Hepadnaviridae family of viruses [103], whereas hep­
and other chemokines [92]. atitis C virus (HCV) is a small, enveloped, positive-sense single-stranded
Chronic induced injury has been confirmed by the observed increase RNA virus of the Flaviviridae family [104]. They are both transmitted via
of inflammatory chemokines (CCL5, CXCL10 and CXCL11) in case of blood or non-sterile needle use (through drug injections, tattoos or
RuV-infected endothelial cells [93]. Interestingly, the chemokine CCL14 medical procedures) or via sexual contacts.
that promotes embryo implantation was down-regulated, as in parallel a Hepatitis B surface antigen (HBsAg) is a particle produced in excess

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during the life cycle of the virus: HBsAg is the first detectable viral an­ All pregnant women should be tested not only for HBV, but also for
tigen to appear during infection but could also be later found, whereas HCV [120]. Prenatal invasive procedures should be minimized in
core antigen (HBcAg) and envelope antigen (HBeAg) are indicators of pregnant women with hepatitis when possible, whereas cesarean section
active viral replication. Anti-HBs antibodies can be detected after sero­ should not be performed for the sole aim to reduce risk of HBV and HCV
conversion or after a successful anti-HBV immunization, while HBV- vertical transmission [121].
DNA is a feasible marker to monitor viral load [105]. The risk of The risk of HBV perinatal transmission is higher when HBV-DNA
Mother-to-Child transmission (MTCT) of HBV is dependent on the viral load exceeds the threshold of 200,000 IU/ml (>106 copies/mL)
timing of exposure: in the case of a HBV-infected mother in the third and could be reduced with any antiretroviral therapy (lamivudine, tel­
trimester, the risk is higher and vertical transmission will occur in 80% bivudine, and tenofovir), started at 28–32 weeks of gestation [122].
to 90% [106]. There is no increased risk of adverse maternal or fetal outcomes,
The presence of HCV-RNA indicates active infection: the risk of although safety data are limited [123]. The use of antiretroviral therapy
vertical transmission of HCV is reduced in women with an undetectable is not recommended when HBV-DNA are lower than 200,000 IU/ml
HCV-RNA, although an intermittent viral load could lead to vertical [122].
transmission [107]. Approximately HCV infection occurs in 6 to 11% of Maternal administration of HBV-specific immunoglobulin can have
infants born to HCV-infected mothers [104]; the risk is greater when an effect on preventing MTCT of HBV, although with a limited evidence
mothers are HIV co-infected [108]. [124]. Infants born to HBsAg-positive women should receive post-
exposure prophylaxis (PEP: HBV vaccination and HBV-specific immu­
2) Mechanisms of fetal damage noglobulin) within 12 h of life. The risk of transmission to the infant
born to a HBsAg-positive/HBeAg-negative mother is low (about 10%) if
Transplacental leakage (related to immature placenta or uterine PEP is correctly given at birth. Conversely, the risk increases up to 90%
contractions), placental infection, and infected maternal peripheral in infants born to HBsAg-positive/HBeAg-positive mothers if not given
blood mononuclear cells (that turn out to be HBV carriers from mother PEP [110]. Infants born to HBsAg-positive mothers should be followed
to fetus) have been described as potential mechanisms for HBV intra­ up for completion of HBV vaccination and postvaccination serologic
uterine transmission, considering that only HBeAg is small enough to testing (PVST), to evaluate effects of immunization and eventually
cross placenta [109]. During pregnancy, significant changes in maternal booster immune response in low-responding infants with further doses
immune system usually occur to avoid rejection of the semiallogenic [117].
fetus. The natural course of HBV infection is influenced by a depressed The risk of HCV perinatal transmission is increased when HCV-RNA
maternal cell-mediated immunity [110], that could stimulate MTCT and viral load exceeds the threshold of 615 copies/mL and rupture of
the development of an immune-tolerant HBV infection in the fetus membrane is longer than 6 h [107]. Ribavirin and interferon are not
[111]. Although acute HBV infection during pregnancy is not associated used in pregnancy because of their teratogenic effects. Direct-acting
with increased fetal mortality or teratogenicity [105], a higher risk of antivirals (DAAs) have not yet approved for use during pregnancy,
gestational diabetes, postpartum hemorrhage, preterm birth, and low although no teratogenic effects have been reported in animals [125]. A
birthweights was reported among complications of HBV infected preg­ phase 1 pharmacokinetic and safety trial (ClinicalTrials.gov number
nant women [110,112]. Vertically HBV-infected infants are usually NCT02683005) evaluated ledipasvir-sofosbuvir use in pregnancy [126]:
asymptomatic and anicteric, but they are likely to have a chronic recruitment was completed in March 2020 but results were not yet
infection afterwards in 90% of cases [113]. published at time of writing. In the absence of an available vaccine
As in other viral infections, human trophoblast cells express cellular against hepatitis C, an accurate screening of infants HCV-exposed during
receptors (Occludin, Claudin-1 and low-density lipoproteins receptor) pregnancy is to be pursued to avoid that many pediatric infections
that HCV use to enter into host cells. This leads to a strong antiviral remain undetected [127], providing a prompt treatment and preventing
response that alters innate immunity at the maternal-fetal interface. thus an early-onset cirrhosis [128].
Furthermore, immunologic changes trigger apoptotic pathway in extra-
villous trophoblast cells, altering placental morphology [114]: this 9. Human immunodeficiency virus
probably plays a key role in pregnancy-related complications: women
with HCV infection are more likely to have stillborn infants [115] or 1) Characteristics of the virus
infants born preterm, with low birthweight or birth defects [116].
Human immunodeficiency virus (HIV) is a member of the genus
3) Diagnosis of congenital infection Lentivirus (within the family of Retroviridae). It has a single-stranded,
positive-sense, enveloped RNA. The virus targets CD4+ lymphocytes,
All pregnant women should be routinely screened for HBsAg: if where it embeds itself into the host cell genome. After entry into the
HBsAg tested positive, a complete assessment including HBV-DNA, HBV lymphocytes, the viral RNA is converted into double-stranded DNA by a
serologic markers and liver function tests should be performed, in order reverse transcriptase, and integrates itself in the host genome, progres­
to identify if any antiviral therapy should be started or not [117]. If sively leading to acquired immunodeficiency syndrome (AIDS) and
HBsAg tested negative and the woman has a high risk to acquire HBV death. Even with the most potent antiretroviral therapy, the virus has
infection (e.g. having an HBsAg-positive sex partner), vaccination been shown to remain latent in peripheral blood monocytes. The
should be performed since pregnancy is not a contraindication [105]. infection is therefore permanent. Two types of HIV have been identified:
At birth, perinatally acquired HBV infection could be confirmed HIV-1, more virulent and globally spread, and HIV-2, lower virulent and
detecting HBV-DNA in neonatal serum. HBsAg and HBeAg could be also confined to West Africa [129]. In most cases, HIV is a sexually trans­
detected, whereas serum aminotransferases are normal or only slightly mitted infection, through blood, semen, and vaginal fluids. Mother-to-
elevated [113]. Child transmission (MTCT) could occur during pregnancy, and not
Similarly, infants born to HCV-positive mothers should be tested via only at delivery, but also in the postpartum period through breastfeed­
HCV-RNA PCR and regularly followed up to 18 months (when clearance ing [130]. Evidence of in-utero transmission of HIV has been demon­
of maternal antibodies is expected) [118]. They should be retested after strated on the syncytiothrophoblast by the presence of cluster of
3 months of age because of possible false-negative results in case of a differentiation 4 (CD4) and CC chemokine receptor type 5 (CCR5) re­
sole earlier testing [119]. ceptors, that the virus uses as coreceptors to enter into cells [131]. HIV
was found in fetal circulation regardless of maternal Highly Active Anti-
4) Prevention strategies Retroviral Therapy (HAART) [131].

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2) Mechanisms of fetal damage trimester: for infants born to mothers with unknown HIV status, a rapid
HIV screening of mothers and/or infants should be performed as soon as
Systemic immune activation begins early after HIV infection, causing possible, either during labor or after delivery, starting immediately the
a chronic inflammation [132], but pregnancy seems to counterbalance appropriate neonatal postexposure prophylaxis (PEP) if the test is pos­
it: Pereira et al. recently described how the placenta keeps the ability to itive [147].
stimulate an intense antiviral network mediated by a pronounced type I Challenges in early diagnosis of HIV include missed or delayed
interferon response, which could limit the vertical transmission at the testing, poor access to care, loss to follow-up but especially mortality
maternal-fetal interface, regardless of HAART, but also lead to immu­ peak in HIV-infected infants. Point-of-care HIV testing of infants with
nological dysfunction of the newborn [133]. Placental macrophages heel-prick sampling could be a solution for some of these problems, in
(Hofbauer cells) seem to be pivotal in in-utero HIV transmission through particular in low-resources settings [148].
constitutive expression of regulatory cytokines, which have been Children with congenital HIV infection are usually asymptomatic at
demonstrated to inhibit HIV-1 replication in vitro [134]. T regulatory birth: symptoms usually occur after 3 months and within 10 years, with
cells (Treg) could also have a role in contrasting MTCT, probably sup­ lymphadenopathy, weight of loss, recurring infections and a progressive
pressing immune activation in fetuses and infants that has been found developmental delay [149,150].
more pronounced in HIV-infected infants [135].
The effect of HAART on maternal HIV-induced inflammation is 4) Prevention strategies
complex: it depends on immunodeficiency and the viral reservoir at the
start of the treatment [136]. Adherence to HAART is crucial in preg­ One of the greatest successes in the field of HIV prevention has been
nancy, although one of the barriers is the fear around side-effects of the prevention of MTCT, using HAART [132]. As mentioned, the virus
these drugs for pregnant women and their fetuses. The association be­ can be detected in peripheral monocytes although not detectable in
tween HAART and adverse birth outcomes is still debated [137]. Specific plasma, therefore the CDC recommends this regimen also for pregnant
congenital defects that were significantly associated with specific drug women with HIV RNA levels below 1000 copies/ml. All pregnant
exposures were male genital (zidovudine and lamivudine), musculo­ women with HIV should be treated with HAART regardless of their
skeletal (atazanavir, ritonavir, and didanosine associated to stavudine), CD4+ count to decrease vertical transmission [146]. Elective cesarean
cardiovascular (atazanavir and ritonavir) and skin (atazanavir) anom­ delivery in HIV-infected women who have not received HAART, when
alies [138] and neural tube defects (dolutegravir) [139]. performed prior to rupture of membranes and the onset of labor, reduces
It is now widely accepted that HAART in pregnancy is associated the vertical transmission rate by 50%. If HIV infection is untreated, the
with increased risk of preterm delivery, but questions remain about the risk of vertical transmission is as high as up to 25%, while is virtually
exact nature of this association, for example how timing of HAART zero in mothers on well-assumed HAART before conception and a sup­
initiation (pre- or post- conception) and maternal immunological status pressed plasma viral load [151].
(e.g. CD4+ T-cell count) are involved [136]. Low birthweight could be Usually HIV-exposed infants receive since birth a zidovudine (ZDV)
also a proxy for preterm birth, but there is a little evidence that HAART PEP, that should be started as earlier as possible, better within 12 h of
exposure during pregnancy influences placental vascular changes and delivery, even if mothers correctly took antiretrovirals. Neonatal PEP
consequently may drive to fetal growth restriction [140]. with ZDV when infants are born to women with undetectable viral load
On the other hand, untreated maternal HIV infection is equally could be shortened to 4 weeks (instead of 6) [152]. If risk of MTCT is
correlated with an increased risk of adverse birth outcomes, such as higher, combination antiretrovirals regimens with two or more drugs
premature delivery, low birthweight/small for gestational age neonates are increasingly preferred without further side effects compared with
and stillbirth, especially in women with advanced HIV disease [137]. ZDV-monotherapy prophylaxis [153].
The evidence for an association of maternal HIV infection with adverse However, there are still many concerns regarding also HEU infants of
perinatal outcomes was still strong in sub-Saharan Africa, where a mothers who correctly received antiretrovirals. HEU infants receiving
greater maternal HIV-1 burden occurs [141]. neonatal PEP with ZDV showed a lower trend (although not significant)
Before HAART, cardiovascular complications occurred in up to 25% in CD4+ and CD8+ T-cells and CD19+ B-cells than those who did not,
of HIV-infected children, with an earlier myocardial dysfunction [142]. suggesting a possible toxicity that could impact their global health
Neurodevelopmental outcomes have been reported as improved if [154]. Growth impairment in infants exposed to any antiretroviral
HAART is offered earlier to HIV-infected infants [143], reducing the regimen should be carefully followed [155].
effects of HIV replication on their immature brain and consequently Anyway, we should keep in mind that, without HAART, 50% of HIV-
future HIV-associated neurocognitive disorders (HAND). infected infants in Africa would die within 2 years of life, compared to a
median survival time of 11 years from time of infection in adults without
3) Diagnosis of congenital infection treatment [156].
To date, besides HAART, obstetrical interventions (such as scheduled
Serologic HIV testing methods are not useful in infants during the cesarean section before labor onset where appropriate) formula feeding
first 18 months because of placental transferring of maternal immuno­ and intrapartum maternal prophylaxis are still the sole viable options to
globulin IgG: even HIV-exposed uninfected (HEU) could test positive. prevent HIV infection in perinatally exposed HIV-infants. None of the
They are generally informative only if the test result is negative [144]. developed HIV vaccines has been approved so far: the calling for the
Virologic assays, including HIV-1 DNA or RNA PCR assays, represent development of an effective and safe vaccine to prevent the infection
the gold standard to diagnose HIV infection in infants [145]. and end the AIDS pandemic remains therefore still open.
A positive HIV-DNA PCR by 48 h of age is the most reliable marker of
in-utero infection: a considerable limitation of this method is the pos­ 10. Parvovirus B19
sibility of false negatives in case of non-B-subtype HIV-1 infections. HIV-
RNA PCR assay is better to use in case of non-B-subtype HIV-1 infections, 1) Characteristics of the virus
although the risk of a false negative test should be considered with an­
tiretroviral prophylaxis [145]. Human parvovirus B19 (B19V) is a member of the genus Eryth­
After birth, infants should thus be tested within first days of life and roparvovirus (within the family of Parvoviridae) and three genotypes have
then again .at 2–3 weeks of age, at 1–2 months of age and at 4–6 months been identified, of whom genotype 1 is the most prevalent and ubiqui­
of age [146]. tous worldwide. It is a non-enveloped, icosahedral virus that contains a
All pregnant mothers should be screened for HIV in the first single-stranded linear DNA. The capsid surface with its two main

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structural proteins (VP1 and VP2) is involved in many functions in the 3) Diagnosis of congenital infection
virus life cycle: specific binding to host cell receptors, internalization
mediated by its phospholipase A2 (PLA2) activity, nuclear entry, and In all infants with fetal hydrops, a B19V infection should be always
recognition and avoidance of the host immune response [157]. In most ruled out. Assessment of Parvovirus B19 infection in pregnant women
cases, B19V is spread through respiratory droplets [158] but could also relies firstly on serology through testing for both B19V specific IgG and
be transmitted vertically through the placenta to the fetus and through IgM antibodies. In general, IgM to B19V appears 7 to 10 days after
transfusion of blood products [159]. The target cell of B19V is the infection, while IgG appear a few days after IgM and then persist for
erythroid progenitor in the bone marrow, through globoside or P blood months or even longer [169].
group antigen, that acts as a cellular receptor, inducing apoptosis and a After a recent exposure, the presence of IgG and the absence of IgM
transient arrest of erythropoiesis [157]. suggest immunity, without any consequence in pregnancy. If IgM is
The common clinical presentation of B19V infection is “Fifth Dis­ present, a possible recent infection should be considered: an accurate
ease”, also known as erythema infectiosum, which occurs mostly in counselling and serial ultrasounds should be performed, in order to rule
healthy children: the typical “slapped cheek” rash implies the clearance out fetal hydrops and predict fetal anemia with Doppler measurement of
of viremia through immune complex formation. Considering the the middle cerebral artery (MCA) peak systolic velocity [170].
adequate red cell lifespan of healthy subjects, no clinical anemia is However, a negative IgM result should also be cautiously interpreted,
usually observed. On the contrary, in patients with chronic hemolytic or considering the risk of false-negative results or a future maternal sero­
sickle cell disease (where red cells' lifespan is shorter), B19V infection conversion [171].
could present with aplastic crises, while pure red cell aplasia (PRCA) Furthermore, several commercial assays have been developed to
occurs in immunocompromised hosts (i.e. HIV/AIDS or after chemo­ detect specific B19V antibodies, not always with the same sensitivity
therapy) [160]. and specificity [172].
Extra-hematological manifestations related to B19V infection have Polymerase chain reaction (PCR) on plasma represent the standard
also been described in adults with arthropathy, glomerulonephritis, method for the molecular detection of B19V DNA and may help to
peripheral nervous system and muscle impairment [161]. determine the stage of infection [172]: viremia occurs as early as 5 to 10
days after exposure, before any change in serology is detected [171].
2) Mechanisms of fetal damage Nonetheless, low viral loads may sometimes persist for a long time.
Invasive prenatal diagnosis of fetal infection involves the use of
Parvovirus B19 vertical transmission occurs in about 30% of cases of amniocentesis: the concentration of B19V DNA has been detected to be
maternal infection [162]. 100 to 5000 times higher in amniotic fluid than in maternal serum and
Differentiating syncytiothrophoblast and cytotrophoblast cells have corresponded to the matching fetal serum [173]. However, diagnosis is
a key role in B19V vertical transmission, because of a strong expression challenging because the presence of viral particles can only be found
of globoside-receptor on their surfaces. Although they are not permis­ during the viremic stage. Furthermore, the detection of B19V IgM in
sive to viral infection, a receptor-mediated transcytosis process leads to fetal blood cannot be used to early diagnose a congenital infection,
release of the virus into fetal circulation [14]. Fetal capillary endothe­ because the fetus does not begin to make its own IgM until 22 weeks of
lium in placental villi could also be an additional target of B19V, leading gestational age [174].
to a structural and functional injury concurring to anomalous maternal-
fetal blood exchanges and to the dissemination of the virus [162]. 4) Prevention strategies
Furthermore, B19V infection of EPCs generates a DNA damage response
by interfering with repair pathways and thus promoting viral DNA Considering that B19V-related fetal damage is primarily due to fetal
replication [163]. anemia, Intra-Uterine blood Transfusion (IUT) represents a life-saving
Once in the fetal circulation, the virus may then spread to fetal procedure in prenatal management of the infection [175].
erythroid precursor cells (EPCs) in the liver and/or in bone marrow, and The overall survival rate in fetuses with severe anemia who required
eventually cardiomyocytes, in the absence of an effective fetal immune IUT is increasing, particularly I the absence of hydrops and if the first
response. The fetus is also more vulnerable considering that the half-life transfusion occurs after a gestational age of >22 weeks [176].
of its red blood cells is short (50–75 days) [164]. However, neurodevelopmental impairment among survivors may
The induced cytotoxic effects and apoptotic mechanisms lead to an occur, even if adequately managed with IUT. Up to 26% survivors pre­
arrest of the marked erythropoiesis of the fetus, resulting in anemia, sented with prenatal abnormal cerebral lesions: an high viral load in
tissue hypoxia, myocarditis, cardiomegaly and pericardial effusion, and fetal blood samples resulted as associated with brain lesions [177].
hydropic or non-hydropic Intra-Uterine Fetal Death (IUFD) [165]. Mechanisms underlying this damage are still unknown: B19V DNA
The peak incidence of B19V-related fetal death occurs early during has been detected in several cerebral areas [178,179] but an hypoxic
pregnancy (within the 20th week) [166], with a lower risk in the second ischemic encephalopathy related to fetal anemia has been hypothesized
half of pregnancy. On the contrary, fetal hydrops, defined as an accu­ [175].
mulation of fluids in at least two fetal compartments (subcutaneous, To date, there is still a gap in the development of antiviral agents
pericardial, pleural, and abdominal), occurs when maternal infection against B19V and although the relatively simple structure of its capsid, a
happens later [165]. Hydrops may eventually lead to IUFD, but vaccine is not available [180].
frequently the fetus can recover without a poor neurodevelopmental
outcome. After birth, mortality associated with hydrops remains high 11. Non-polio enteroviruses
despite advances in treatment, especially in preterm infants [167].
Thrombocytopenia may accompany severe anemia, as a result of 1) Characteristics of the virus
megakaryocyte destruction: fetal hemorrhage was not seen as a
complication of thrombocytopenia [168]. Enterovirus (EV) is a genus of positive-sense single-stranded RNA
B19V seems to be not teratogenic. However, further studies are viruses, belonging to Picornaviridae family. Historically, poliomyelitis
needed to conclude if other fetal abnormalities associated with B19V was the most worrying disease caused by an enterovirus, namely
infection (meconium peritonitis, ocular injuries, brain lesions such as poliovirus (types 1 to 3), become exceedingly rare in most developed
parenchymal calcifications, arterial infarction, cerebellar hemorrhage, countries as a result of routine immunization programs. There are 81
hydrocephalus and polymicrogyria) are rare or not [3,164]. non-polio human enteroviruses (EVs): 22 Coxsackie A viruses (CV A1 to
A21, A24), 6 Coxsackie B viruses (CV B1 to B6), 28 echoviruses (ECV 1-

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C. Auriti et al. BBA - Molecular Basis of Disease 1867 (2021) 166198

7, 9, 11-21, 24-27, 29-33), and 25 other enteroviruses (EV 68-71, 73-91, early identify the cause of severe neonatal infections.
100-101) [181]. There are still no available vaccines: potential vaccines still remain in
EVs infections in the neonate are associated with a wide spectrum of the initial stages of development [193]. Recently, Wei et al. studied the
signs and symptoms, which range from a non-specific febrile illness to transfer and decay of maternal antibodies against EV-A71: antibodies
potentially fatal multisystem disease, frequently referred to as ‘neonatal were efficiently transferred to neonates but declined quickly to below
enterovirus sepsis’ or ‘enteroviral sepsis syndrome’ [182]. Common the protective threshold. Maternal vaccination could be explored to
findings include fever or hypothermia, irritability, lethargy, anorexia, provide neonatal protection against EV-A71 through maternal anti­
rash (“hand, foot and mouth disease”), jaundice, respiratory symptoms, bodies, whereas catch-up vaccination between ages 6 months to 5 years
apnea, hepatomegaly, abdominal distension, emesis, diarrhea, and could provide protection afterwards [194]. A phase III clinical trial has
decreased perfusion [183]. Most EVs cases have a benign course, been planned to evaluate the efficacy, safety, and immunogenicity of a
whereas some have a severe presentation, including sepsis, meningo­ vaccine against EV-A71 at this age, but it is still not recruiting (Clin­
encephalitis, myocarditis, hepatitis, coagulopathy, and pneumonitis icalTrials.gov number NCT03865238).
[183,184]. Neurotropism of EVs still represents a continuous threat to
public health, with aseptic meningitis, encephalitis, acute flaccid pa­ 12. Severe acute respiratory syndrome coronavirus 2
ralysis [185].
1) Characteristics of the virus
2) Mechanisms of fetal damage
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is
Evidence suggests that EVs infections can be acquired antenatally, the virus that causes coronavirus disease 2019 (COVID-19), the respi­
intrapartum and postnatally. In-utero transmission in late gestation has ratory illness responsible for the ongoing pandemic. It is a newly
been demonstrated in animal models [186], despite the predominant discovered β-Coronavirus with a positive-sense single-stranded RNA
mode of transmission of neonatal infection (63%) is intrapartum, at the virus, belonging to Coronaviridae family. The first step in SARS-CoV-2
time of delivery through contact with maternal blood, stool, amniotic infection is the invasion of a host cell, a process that is mediated by
fluid, or vaginal or cervical secretions [183]. Postnatal transmission the spike (S) glycoprotein. SARS-CoV-2 structural proteins also include
after exposure to oral secretions of mother and other family members is the nucleocapsid protein (N), the membrane protein (M) and the enve­
relatively common. Liu et al. explained the role played by specific host lope protein (E) [195].
cell surfaces receptors, called Coxsackie-Adenovirus Receptors (CARs), This novel virus has a strong capacity to spread, mainly via droplets
that seemed to be necessary for coxsackieviruses attachment and entry and aerosols during close unprotected contacts, with an incubation
into cells, and accounts for organ and age-specific susceptibility to period ranging from 2 to 14 days. It can be easily detected by Real Time
infection. It has been postulated that the lack of expression of these Polymerase Chain Reaction (RT-PCR) in nasopharyngeal swabs [196].
receptors in the placenta may help to prevent vertical transmission of Most infections are uncomplicated, but some patients could require
the virus to the fetus [187]. The role of a co-factor such as Decay- admission to intensive care unit because of respiratory and multiorgan
accelerating factor molecule has been studied for interaction with CV- failure. Risk factors for complicated disease are advanced age (>50
B3: this cofactor blocks the CAR binding site and causing the two re­ years), male sex and comorbidities (especially hypertension, diabetes,
ceptors to complete themselves [188]. cardiovascular disease, chronic pulmonary disease, acute kidney injury)
Regarding Enterovirus 71 (EV-A71) infection, Feng et al. demon­ [197]. Neonatal and pediatric cases are principally family cluster cases
strated in a mouse model that the CNS damage in neonatal cases might [198]; most of them have epidemiological links to adult subjects, and
be caused by an activated fetal cerebral immune response to the virus, show only milder clinical symptoms [199].
including the disruption of brainstem function through increased levels
of cytokines and neurotransmitters, rather than just a cytopathic effect 2) Mechanisms of fetal damage
of viral infection [189].
The SARS-CoV-2 virus links itself through its spike protein to the
3) Diagnosis of congenital infection receptor of the angiotensin-2 converting enzyme (ACE2), that is
expressed on the membrane of many host cells, including placental ones.
RT-PCR has been shown to be far more sensitive than cell culture for It is widely expressed, in particular on syncytiothrophoblasts, hypo­
detection of EVs in clinical samples. Although specific IgM and IgG as­ thetically being able to contribute to the transplacental transmission of
says for EVs have been described and are available, their clinical utility the virus to the fetus during maternal infection [200]. In addition, the
is limited due to the cross-reactivity of the antigens used among the co-expression of transmembrane protease serine 2 (TMPRSS2) can foster
different serotypes [190]. Most EVs cases occur from 3rd to 5th day of the entry by stimulating the fusion of viral particles with the host cell-
life, suggesting that the timing is likely related to the immediate peri­ membrane and related viral replication [201]. Similar to other RNA
natal period. Risk factors include maternal illness within a week of de­ viral infections in pregnancy, the presence of placental lesions due to
livery, with acute fever and severe lower abdominal pain, often SARS-CoV-2 infection has been described by a large study, with fetal
misdiagnosed as placental abruption or appendicitis [182], prematurity and/or maternal vascular malperfusion and inflammation signs,
and absence of specific antibodies to the infecting serotype in the although all infants of infected mothers tested negative on RT-PCR and
neonate [183]. The timing of infection and the type of virus influence were asymptomatic [202]. Furthermore, the virus can be present in the
the clinical presentation, considering the typical tissue tropism of placenta with a viral load at least two-fold higher that of the maternal
certain EV. Disseminated infections with CVs and ECVs could frequently blood and nasopharynx, increasing the eventual risk of intrapartum
involve the CNS [191], perhaps due to viremia. CVs and ECVs can also transmission [203].
cause myocarditis, and therefore, intrauterine infection with enterovi­ The theoretical risk of vertical transmission has therefore a biological
ruses should be considered in the differential diagnosis of non-immune plausibility, but a caution is recommended in the interpretation of data,
hydrops fetalis [192]. due to lack of collection of appropriate specimens from all tissues of both
mother and infant at appropriate times and data still related more often
4) Prevention strategies to case reports and series rather than to large multicenter studies.
Most cases are related to infection contracted in the third trimester or
No specific intervention is available for pregnant women, but a his­ in the peripartum, when maturation of most organs is already
tory of relevant symptoms with fever and diarrhea may help clinicians to completed, whereas no cases of infections contracted early in pregnancy

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with confirmed teratogenic effects have been reported [204]. Overall emphasizes how international strategies of surveillance and tracking
rate of malformations in women with SARS-CoV-2 infection resulted to could tackle this moving target [213].
be similar to non-infected women, according to data from a Spanish Everyday preventive actions to reduce the spread of COVID-19,
multicenter study [205]. including social distancing, protective masks, and hands hygiene still
In a systematic review about effect of COVID-19 on pregnancy and remain key elements of this struggle.
perinatal outcomes, only four cases of spontaneous miscarriage or Our hope is that always more vaccine doses would be available and
abortion (1.4%) were reported [206]. administered as soon as possible; furthermore, we hope that current
Transcriptome models showed that ACE2 expression changes over vaccines could provide an effective prolonged protection, beyond a few
time in placental, fetal, and neonatal tissues increasing between the end changes at antigenic sites in SARS-CoV-2 new variants.
of gestation and the first days of postnatal life [207]. This would justify Data on the safety of COVID-19 vaccines in pregnant women and
the lack of reports describing negative outcomes of maternal infection in during breastfeeding are still limited. However, many pregnant women
the early stages of gestation, although we cannot yet exclude that they have decided to accept to be vaccinated [214]. By monitoring the out­
exist. However, it would be argued that transplacental transmission is comes for these women and their infants, first data reported a maternal
possible or more likely in the last weeks of pregnancy. Vivanti's recent immune response and transfer of maternal antibodies to confer passive
report seems to have demonstrated neonatal viremia, following immunity against SARS-CoV-2 in neonates after maternal vaccination
placental infection: the placenta showed signs of acute and chronic with mRNA-based vaccines (BNT162b2 Pfizer/BioNTech or mRNA-
intervillous inflammation consistent with the severe systemic maternal 1273 Moderna/NIH) [215,216].
inflammatory status triggered by SARS-CoV-2 infection. Both maternal
and neonatal blood samples were positive, and the newborn presented 13. ZIKA virus
symptoms similar to infected adults [208].
1) Characteristics of the virus
3) Diagnosis of congenital infection
Zika virus (ZIKV) is a member of the genus Flavivirus (within the
In a recent systematic review and meta-analysis of 176 published family of Flaviviridae), related to dengue virus (DENV), yellow fever
cases of neonatal SARS-CoV-2 infections, only 5.7% of cases were clas­ virus (YFV), Japanese encephalitis virus (JEV), Chikungunya virus
sified as confirmed congenital infections [209]. (CHIKV) and West Nile virus (WNV). It is a enveloped and icosahedral
Recently, a panel of the World Health Organization (WHO) including virus that contains a single-stranded, positive-sense RNA; it is spread by
experts of all involved fields proposed a consensus about classification daytime-active Aedes mosquitoes (such as A. aegypti and A. albopictus),
system of vertical transmission of SARS-CoV-2, to allow comparison of sexual contacts, blood transfusions, and vertical transmission [217].
data from different studies and better understand clinical consequences Two receptors, AXL tyrosine-protein kinase receptor and T-cell immu­
for the neonates born to infected mothers [210]. noglobulin and mucin domain 1 (TIM1) receptor, were suggested as
Firstly, they classified the timing of vertical transmission (in-utero, candidates for ZIKV entry in vitro, while their role in vivo is still to fully
intrapartum and early postnatal) in mutually exclusive categories, as explain [218].
follows: (a) confirmed; (b) possible (evidence is suggestive but not In most of the cases, ZIKV infection is asymptomatic (up to 80%)
confirmatory for infection); (c) unlikely (little support for diagnosis but [219]; after an incubation period of 3 to 14 days, sometimes patients
infection cannot be completely ruled out); and (d) indeterminate (when experience a maculopapular rash, low-grave fever, myalgia/arthralgia,
tests required to define classification have not been performed). An in- headache, and conjunctivitis [220]. In adults, ZIKV infection has been
utero infection can be defined as confirmed if there is 1) “evidence of associated with neurological disorders (such as Guillain-Barré syndrome
maternal infection” anytime during pregnancy and 2) “in-utero fetal and acute myelitis), ocular disorders (hypertensive iridocyclitis, mac­
exposure” (when at least one neonatal sample tests positive for SARS- ulopathy, uveitis), thrombocytopenic purpura and transient myocarditis
CoV-2 within 24 h of life) and 3) “SARS-CoV-2 persistence or immune [221].
response in the neonate” (at least one neonatal sample test positive again Conversely, the 2015–16 outbreak of Zika virus brought the world's
at 24–48 h of life). attention to links between ZIKV infection and microcephaly in fetuses
The presence of the criterion of viral persistence/immune response and neonates born to women infected during pregnancy [222].
in the neonate after 24 h of life is fundamental because a single positive Among exposed fetuses, fetal loss occurred in 14% and severe com­
RT-PCR early obtained on a neonatal respiratory sample may indicate plications compatible with Congenital Zika Syndrome (CZS) occurred in
either active viral replication, viral fragments intrapartum or postnatally 21% [221]. To date, although ZIKV particles have been detected in
acquired, or just a contamination. human milk, breastfeeding has not been confirmed as a transmission
Conversely, most of neonatal SARS-CoV-2 cases are postnatally ac­ route and mothers with possible or confirmed ZIKV infection are rec­
quired: infants may be exposed to the virus from their mother, health­ ommended to keep breastfeeding their babies [223].
care workers or other family members, making the source of infection
difficult to assess. Despite the finding of viral particle in human milk, 2) Mechanisms of fetal damage
breastfeeding resulted as not associated with SARS-CoV-2 infection
[209] and this suggests that viral transmission through the milk, if any, Maternal ZIKV exposure induces to a diffuse placental injury, with
should be rare. Therefore, mothers with suspected or confirmed COVID- trophoblast hyperplasia, focal regions of necrosis, and loss of embryonic
19, if they are in good clinical conditions, can breastfeed their babies, by blood vessels: these changes probably promote adverse fetal outcomes,
mandatorily applying all correct hygiene rules [211]. even in the absence of fetal infection [224]. An increase in the number of
macrophages and Hofbauer cells has been observed, promoting the
4) Prevention strategies production of matrix metalloproteinases that degrade the collagen (as
well as TNF-α) and activate immune cell trafficking. CD68+ and T CD8+
At time of writing, available vaccines have given us a first hope, but cells were largely detected in infected placentae, with an high expres­
the fight against COVID-19 is not over yet. The emergence of new var­ sion of cytokines (IFN-γ and TNF-α) and other immunological mediators
iants with a higher spreading capability (such as B.1.1.7 from United (RANTES/CCL5 and VEGFR-2) that confirmed excessive inflammation
Kingdom, B.1.351 from South Africa, P.1 from Brazil and B.1.617 from and vascular permeability dysfunction [225]. Furthermore, in the
India) is an expected occurrence, considering that RNA viruses usually presence of ZIKV infection, Bcl-2 protein has been showed to be over­
have an higher incidence of mutations than DNA viruses [212]. This expressed in the third trimester syncytiothrophoblast cells, leading to a

11
C. Auriti et al. BBA - Molecular Basis of Disease 1867 (2021) 166198

higher cellular apoptosis and persistence of viral particles in placenta choice in stable couples [239].
[226].
After breaching the maternal-fetal interface, the virus reaches the 14. Conclusion
developing brain by hematogenous route or via the cerebrospinal fluid,
where increased specific immunoglobulins levels have been recently The placenta is a immune-tolerant environment, in continuous
demonstrated in neonates exposed to Zika during fetal life [227]. development during gestation that allows viruses to replicate. The in­
AXL receptor seems to be the primary ZIKV entry cofactor on human fectious power of viruses varies in relation to the characteristics of the
umbilical vein endothelial cells (HUVECs), allowing to the virus to enter developmental stage of the placenta, generating fetal damage of
the fetal bloodstream to gain access to other fetal tissues [228]. How­ different severity or no damage. The mechanisms of this placental bar­
ever, other receptors may also contribute to the entry of the virus, rier function are not fully understood, for both known and emerging
considering that AXL resulted to be not fundamental for vertical trans­ viruses. Oxygen levels certainly constitute an up-regulation factor of
mission in mice [229]. adhesion receptors, which are cofactors of infection. The vascular bed is
AXL mRNA has also been found in human neural progenitor cells forming, and the development of new vessels allows lymphocytes to
(NPCs) and other brain cells (such as radial glial cells, microglial cells enter, carrying viruses. Furthermore, the placental is a low resistance
and astrocytes), suggesting a susceptibility of these cells and explaining vascular area and this facilitates the entry of viruses into the intervillous
related brain abnormalities [230]. space.
Pro-inflammatory state in the fetal brain has been recently confirmed The problem is complex, but the greater the knowledge, the more
by increased immunoglobulins levels in cerebrospinal fluid in neonates. effect the prevention strategies of neonatal damage will have, as has
been shown by the history of HIV, the better the weapons will be to face
3) Diagnosis of congenital infection the challenges of new viruses, whose probability of emergence will be
proportional to the climatic damages, that we will bring to the envi­
Pregnant women with ZIKV infection should be serially screened, ronment around us.
although prenatal ultrasound examination cannot always detect CZS
abnormalities [231]. Specific IgM can be detected in the mother as early
CRediT authorship contribution statement
as 4–5 days post-infections and for up to 12 weeks; after exposure, a
negative IgM ELISA test is strongly related to the absence of a recent
CA and DUDR drafted the section on SARS-CoV-2 and ZIKV; DUDR
infection [232]. While amniocentesis is useful for diagnosing other fetal
drafted the section on RuV, HIV and B19V; DUDR and AS drafted the
viral infection, the need of testing amniotic fluid to detect ZIKV RNA is
section on HBV and HCV; FS drafted the section on VZV; IB drafted the
still debated [233].
section on CMV; IB and LM drafted the section on HSV; DUDR and MPR
Key features of CZS include both structural lesions and functional
drafted the section on HHV-6; MPR drafted the section on EV.
anomalies. A fetal brain disruption sequence is typically observed,
CA integrated all authors' contributions: the draft was then reviewed
including severe microcephaly, premature closure of the fontanels and
and critically revised by all authors.
partial collapse of the skull. Brain abnormalities include cortical thin­
ning, hypoplasia of the cerebellum vermis, dysgenesis of the corpus
callosum and gyral anomalies, linear calcifications (mainly subcortical), Funding
ventriculomegaly and increased pericerebral spaces [221]. Ocular ab­
normalities should also be ruled out: posterior pole focal pigment None.
mottling of retina, chorioretinal atrophy in the macular area, optic nerve
abnormalities (such as optic nerve hypoplasia and severe optic disc
cupping) were the prevalent lesions observed in Brazil [234]. A typical Declaration of competing interest
“femur-sparing” profile of intrauterine growth restriction (IUGR) could
be observed in infected fetus at ultrasound scans, with an arrest of fetal The authors declare that they have no known competing financial
head growth while the long bones (i.e. femur) continue to grow nor­ interests or personal relationships that could have appeared to influence
mally [235]. the work reported in this paper.
The absence of clinical and neuroradiological CZS abnormalities at
birth does not exclude future functional implications for both the References
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