FETAL AND NEONATAL INFECTIONS
Fetal and neonatal
infections
Stefania Vergnano
Paul T Heath
Abstract
Several organisms cross the placenta, causing infections in the fetus
that manifest differently depending on the organism and the time of
acquisition during pregnancy. Neonates are relatively immunocompro-
mised, and prematurity increases the risk of infection. Newborns ac-
quire infections during delivery and breastfeeding (vertical infections)
or in the neonatal period from the environment (horizontal acquisition).
Hospital-acquired infections are common in neonatal intensive care
units and can pose serious infection control issues. This chapter ad-
dresses the most common agents causing congenital and neonatal in-
fections, their clinical manifestations, management and prophylaxis.
Keywords CMV; cross-infection; fetus; GBS; HSV; MRCP; newborn;
sepsis; syphilis; Toxoplasma; VZV; Zika
Infections in the fetus e intrauterine infections
Several pathogens affect pregnant women and can cause disease
in the fetus. These range from early intrauterine death resulting
in miscarriage and stillbirth to intrauterine growth restriction
(IUGR), congenital malformations and congenital infections. In-
fections in the first trimester are generally more likely to cause
severe defects and can result in stillbirth. Infants can be symp-
tomatic in early life, or symptoms and signs can manifest later in
life (Table 1). These protean manifestations depend on the or-
ganism, the time of infection in relation to the pregnancy and
maternal immune status.
Pathogenesis
Infectious agents can affect the developing fetus in different ways
(Figure 1):

by infecting the placenta and interfering with fetal nutri-
tion and gas exchange, causing intrauterine death and
compromising fetal growth (IUGR) (e.g. placental malaria)

by compromising the development of specific organs for
which the organism has a specific tropism (e.g. rubella)

by infecting the fetus (e.g. hepatitis B or HIV).
The likelihood of an organism affecting the fetus depends on
the time of acquisition during pregnancy and varies with
Stefania Vergnano MRCPCH PhD is a Consultant in the Paediatric
Infectious Diseases and Immunology, Bristol Royal Hospital for
Children, UK. Competing interests: none declared.
Paul T Heath FRCPCH is Professor of Paediatric Infectious Diseases
at the Vaccine Institute and Paediatric Infectious Disease Research
Group, St George’s, University of London, UK. Competing interests:
none declared.
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Key points
C Oral valganciclovir is now recommended for 6 months to treat
congenital CMV infections when diagnosed in the newborn
period
C A new congenital syndrome likely to be caused by Zika virus
has been described and is characterized by microcephaly and
CNS abnormalities, travellers to the affected countries needs
to be counselled about the need for barrier contraception
methods
C The incidence of herpes simplex virus is increasing. New pro-
phylaxis guidelines have been recently published
C In low- and middle-income countries, neonatal infections are
responsible for just under 1 million deaths in the under-5s. In
high-income countries, hospital-acquired infections are more
common in neonates than any other age group. Emergence of
antimicrobial resistance needs to be considered when empir-
ical antibiotic choices are made
different pathogens: congenital toxoplasmosis is more likely if
infection is later in pregnancy (30e75%), while rubella trans-
mission occurs early.
The mother’s immune status is important, and primary
infection during pregnancy is associated with a high likelihood of
fetal involvement. In the case of rubella, where the risk of
transmission to the fetus is limited to the first infection and an
effective vaccine is available, congenital infections have almost
disappeared in high-income countries.
The most common congenital infection in high-income
countries is currently cytomegalovirus (CMV; the incidence of
congenital CMV in the UK is three per 1000). Worldwide, HIV
and syphilis are the most common congenital infections, with
about 330,000 new HIV infections per year and about 500,000
adverse pregnancy outcomes resulting from syphilis each year.1
In 2015, Zika virus infection was linked to a newly described
congenital syndrome characterized by microcephaly, although
causality has yet to be conclusively proven. Zika cases in adults
have currently been reported in more than 80 countries.
Clinical manifestations, investigations and
management
The clinical manifestations of congenital infections are variable.
Infection during the early stages of pregnancy severely compro-
mises embryogenesis and can result in fetal demise, congenital
malformations and fetal growth restriction, resulting in IUGR.
Infections later in pregnancy can result in asymptomatic babies
at birth who might remain asymptomatic or progress to develop
signs of infection at a later stage. Pathogens can cause a
constellation of signs such as rashes, lymphadenopathy, hep-
atosplenomegaly, jaundice and intracranial calcifications. Char-
acteristic congenital malformations are described for some
infections (Table 1).
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 FETAL AND NEONATAL INFECTIONS

Congenital infections
Viruses Time of acquisition Maternal immunity Manifestation at birth Treatment and prevention

Cytomegalovirus Mostly during third Primary infection > Asymptomatic (90%) Oral valganciclovir for 6 months if
(CMV) trimester reinfections Blueberry muffin, petechial rash, congenital CMV is diagnosed in the
hepatosplenomegaly, microcephaly, ocular neonatal period and the infant is
involvement, intracranial calcifications, symptomatic
jaundice, thrombocytopenia, abnormal liver
function tests
Later development of hearing loss
HIV Mostly during delivery Risk increases with Asymptomatic or lymphadenopathy, Highly active antiretroviral
and breastfeeding high viral load and hepatosplenomegaly combination therapy in mothers
low CD4 cell count and avoidance of breastfeeding
where safe, affordable and
sustainable, exclusive
breastfeeding if not possible
Hepatitis B Typically chronic Risk of transmission: Asymptomatic Vaccination at birth if mother
carriage in mother HbSAgþ HbeAge: 5 HbSAgþ HbeAge
e20% Passive and active vaccination at
HbSAgþ HbeAgþ: 70 birth if HbSAgþ HbeAgþ
e90% Prevention: vaccination
Zika virus Unknown Likely primary Microcephaly, cortical atrophy, brainstem Prevention of infection in
infection abnormality, craniofacial disproportion, pregnancy through avoidance of
seizures, spasticity, cardiac malformations, travel to high-risk areas, protection
digestive system malformations against mosquito bites, avoidance
of pregnancy
No treatment is available
Parvovirus B19 Mostly during the first Primary infection Hydrops fetalis There are case reports of successful
20 weeks Anaemia intravenous Ig use for treatment
Varicella-zoster Mostly during the first Primary infection Asymptomatic, congenital scarring of the Prevention:
20 weeks skin, cutaneous defects, bullous lesions, C Vaccination before pregnancy
asymmetrical limb hypoplasia and C Varicella-zoster Ig after
autonomic dysfunction, eye defects, exposure
seizures and mental retardation
Bacteria
Rubella Mostly in the first Primary infection Asymptomatic, IUGR, thrombocytopenic Prevention: vaccination before
trimester (80%) purpura, hepatosplenomegaly, pregnancy
lymphadenopathy, jaundice, eye
involvement, cardiac abnormalities,
pneumonitis, meningo-encephalitis, bone
lesions, cryptorchidism, haemolytic anaemia
Progressive disease in some cases
Treponema From 14 weeks’ Primary infection 70 Asymptomatic Parenteral benzylpenicillin for 10
pallidum gestation, risk e100% transmission Petechial, vesciculo-bullous or macular rash days
increases Secondary infection affecting also palms and soles,
progressively 40% transmission hepatosplenomegaly, lymphadenopathy,
rhinorrhoea, jaundice, anaemia, CSF
abnormalities, bone abnormalities on X-ray
Mycobacterium Rare, transmission can Asymptomatic Quadruple antimycobacterial
tuberculosis be in utero and at Miliary tuberculosis therapy
delivery

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 FETAL AND NEONATAL INFECTIONS

Table 1 (continued )
Viruses Time of acquisition Maternal immunity Manifestation at birth Treatment and prevention

Protozoa
Toxoplasma Highest risk if Mostly primary Asymptomatic to IUGR, hepatosplenomegaly, Pyrimethamine and sulfadiazine þ
infection acquired late infection but petechiae, skin rash, pneumonitis, diarrhoea, folinic acid
in pregnancy (5e15% congenital infections hypothermia, intracranial and hepatic cranial Prevention: avoid raw meat and
risk in first trimester, described following calcifications, eye involvement, encephalitis wash hands if any risk of contact
25e40% in second, reactivations with or without seizures, hearing impairment. with cats’ faeces
30e75% in third) Triad: chorioretinitis, intracranial
calcifications, hydrocephalus

Ig, immunoglobulin; IUGR, intrauterine growth restriction; CSF, cerebrospinal fluid.

Table 1

Transmission routes of congenital and neonatal infections

Maternal infection

Transuterine
Haematogenous Breastfeeding
and birth canal

Fetal/congenital infection Neonatal infection

First Second Third

Birth
trimester trimester trimester

Environment
Toxoplasmosis

Rubella

Syphilis

Cytomegalovirus

Herpes simplex virus

HIV

Risk of infection
Severity of infection
For HIV the risk of postnatal transmission through breastfeeding depends on the maternal viral load and the neonatal
mode of feeding.

Figure 1

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 FETAL AND NEONATAL INFECTIONS
Investigations should be prompted by severe IUGR, intracra-
nial calcifications and/or clinical manifestations in young infant.
A high index of suspicion for congenital infection can also be
appropriate for certain manifestations in older infants. An accu-
rate history of the pregnancy and scrutiny of antenatal test results
are needed, and appropriate investigations should be initiated.
The initial screening for congenital infections needs to be
directed by the clinical manifestations and can include a urine
sample for CMV DNA polymerase chain reaction (PCR), serology
for rubella and Toxoplasma (immunoglobulin M (IgM) in the
infant), Venereal Disease Research Laboratory (VDRL) test and
specific treponemal tests. If there is a history of living or travel-
ling during pregnancy to countries where Zika virus is reported,
testing should be recommended, particularly if microcephaly is
detected during antenatal scans.
Prevention and treatment are disease specific and depend on
accurate diagnosis.
Four congenital infections (CMV, congenital toxoplasmosis,
Zika virus and syphilis) are detailed below; HIV and hepatitis are
discussed elsewhere.
Cytomegalovirus
CMV is the most common congenital infection in high-income
countries and is responsible for about 25% of sensorineural
hearing loss.
Transmission is 40 times more common in mothers acquiring
CMV in pregnancy for the first time than for reinfections. The risk
of transmission is highest if infection occurs during delivery, and
it can also be acquired through breastfeeding (postnatally ac-
quired CMV infection). Premature infants are at highest risk of
infection from breast milk.
Although 90% of congenital infections are asymptomatic at
birth, progressive sensorineural hearing loss develops in 5e10%
of cases during childhood. The characteristic clinical manifesta-
tions are listed in Table 1. Postnatally acquired CMV infection is
mostly asymptomatic but can present with hepatosplenomegaly,
jaundice, pneumonitis and sepsis-like syndrome. Diagnosis is by
urine or saliva CMV DNA PCR. Blood PCR is less sensitive.
Distinguishing between congenital and acquired disease can be
problematic. Laboratory evidence of infection within the first 3
weeks of life is generally believed to reflect a congenital infection.
Guthrie card testing is helpful, when positive, to confirm congen-
ital infection. Infants with proven congenital CMV infections,
diagnosed within the neonatal period, are currently treated for 6
months with oral valganciclovir; intravenous ganciclovir can be
used until oral valganciclovir is tolerated. If the diagnosis of
congenital CMV occurs after the neonatal period, no treatment is
advised.2 A study is underway to establish whether oral valgan-
ciclovir is effective when started after the neonatal period.
Congenital toxoplasmosis
Congenital toxoplasmosis is rare in the UK and North America,
with an adult seroprevalence of 10e30%. In Southern and Cen-
tral Europe, the seroprevalence is higher (30e50%), and
congenital infection is more common. Prevention is through
counselling of pregnant women to avoid eating undercooked or
raw meat, wash hands thoroughly after gardening and avoid
clearing cat litter. In some countries, routine screening in preg-
nancy is undertaken.
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Fetal infection occurs mostly during primary maternal infec-
tion, and the risk of transmission increases as pregnancy prog-
ress (Figure 1). The degree of fetal compromise is, however,
greater in the first trimester and progressively diminishes.
Diagnosis during pregnancy is through serology in symp-
tomatic women, or during routine screening. Serology requires
careful interpretation, and the toxoplasmosis reference labora-
tory can be contacted for advice. Positive IgM with negative IgG
is indicative of recent infection. Confirmation with repeat IgG,
IgM with or without IgA titres and a IgG avidity test is, however,
essential.
Once the diagnosis has been established in pregnancy, it is
necessary to ascertain whether the fetus is infected, through
molecular testing or culture of amniotic fluid. Amniocentesis
should be performed after 18 weeks, and at least 4 weeks from
the primary infection. Serial fetal ultrasounds are also indicated.
Termination of pregnancy can be offered.
Spiramycin is used to reduce the risk of transmission to the
fetus in the first trimester. Spiramycin is unlicensed in the UK
because there is not enough evidence to recommend its use at
present, as there are no randomized controlled studies available.
When fetal or maternal infection is confirmed later in pregnancy,
the preferred treatment is pyrimethamineesulfadoxine with
folinic acid.
At birth, the infant requires thorough clinical examination for
signs of congenital infection, including ophthalmological
screening and brain imaging (Table 1). Diagnosis is confirmed by
molecular testing (PCR) and serology from blood, cerebrospinal
fluid (CSF), urine or placenta. In the case of proven or highly
suspected infection, pyrimethamineesulfadoxine and folinic acid
are commenced and treatment is continued for 1 year. Close
monitoring of the white cell count is necessary. On completion of
treatment, ophthalmological monitoring is for life as ocular le-
sions might progress and require further treatment.
Syphilis
Congenital syphilis is a preventable disease; however, it is esti-
mated to cause at least 520,000 adverse fetal outcomes per year
globally in terms of stillbirths, early deaths and congenital in-
fections. This is mostly because of a lack of maternal screening
and treatment. In high-income countries, screening is routinely
undertaken, but it can still result in incomplete or inadequate
treatment and lack of infant follow-up, particularly in travellers
and the most deprived social groups, in whom non-attendance to
follow-up appointments is high.
The most common clinical manifestation of fetal infection is
abortion or stillbirth. Signs of congenital syphilis are listed in
Table 1. A high proportion of women with primary or secondary
untreated syphilis are likely to transmit the infection and need
treatment with penicillin G at least 1 month before birth.
The evaluation of infants who are born to known positive
mothers includes obtaining detailed clinical assessment and
serology such as the VDRL test and specific anti-treponemal
serology tests such as the enzyme immunoassay (EIA) or the
Treponema pallidum particle agglutination test (TTPA). A lum-
bar puncture should also be considered; a positive VDRL test,
high protein and elevated white cell count are suggestive of
central nervous system (CNS) infection. In mothers with un-
known antenatal syphilis serology a high index of suspicion
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 FETAL AND NEONATAL INFECTIONS

needs to be maintained and serology obtained. Point of care Causality has not been confirmed; however, viral tropism for
testing exist and are widely used in low and middle-income the CNS demonstrated in animals, isolation of the virus from the
countries. CNS of affected fetuses, confirmation of infection in pregnant
The gold standard antibiotic for treatment is benzylpenicillin, women carrying infants with microcephaly and epidemiological
given for 10e14 days. Infected infants should be followed up at increase of microcephaly in Brazil at the time of the Zika
regular intervals of 3 months until serology becomes negative. In epidemic all clinically point to Zika as a cause for this congenital
2014, the World Health Organization launched a campaign to syndrome.
eliminate congenital syphilis, and this gained some momentum Zika virus is a flavivirus transmitted by Aedes spp. mosquitoes
when coupled with prevention of mother to child transmission of in tropical, subtropical and temperate areas in more than 80
HIV (PMTCT) in 2014. countries to date. The virus is present in blood and other bodily
fluids, including semen. Sexual transmission has been described. A
Zika virus mild viral infection after 4e8 days’ incubation develops in adults,
An increased number of infants born with microcephaly (<2 SD with an itchy rash, non-purulent conjunctivitis, fever, arthralgia
for age) in association with a Zika virus outbreak in Brazil in and sometimes myalgia and abdominal symptoms. Carriage in
2015, and a similar finding retrospectively identified in the semen can persist for prolonged periods, therefore couples travel-
French Polynesia epidemic in 2013e2014, raised the possibility ling to areas at risk needs to be counselled about using effective
of a causal association between the virus and a new congenital barrier contraception also on return from the affected areas.
syndrome. The diagnosis of congenital Zika syndrome requires the
Congenital Zika syndrome is associated with craniofacial exclusion of other causes of congenital abnormalities, a sugges-
disproportion, seizures, spasticity and brainstem abnormalities, tive exposure history and confirmation of the virus by molecular
such as feeding difficulties, vision and hearing defects. An diagnosis (PCR) or serology.
increasing number of brain abnormalities are being reported, It is currently not clear when in pregnancy the risk of mother-
such as subcortical calcifications, cortical malformation, retinal to-child transmission is highest.3
abnormalities, cerebral atrophy, neuronal migration defects and
ventriculomegaly. Other organs can also be involved, with car- Infections acquired intrapartum or during the neonatal
diac and digestive system abnormalities (Table 1). period
Neonates are immunocompromised for many reasons: their skin
and mucous membranes are thin and provide a weak barrier to
Common bacteria and fungi causing neonatal infections infections, and their immune system is immature with regard to
both specific and innate immunity.
Community Hospital Neonates born prematurely are at even higher risk of infections
acquired acquired as, additionally, they lack protection by maternally derived anti-
EO LO LO bodies. The transplacental passage of maternal IgG occurs mostly
in the last trimester of pregnancy, and the acquisition of maternal
Gram-positive
IgA through breast milk is often not possible because clinical cir-
Group B streptococci þþþ þ þ
cumstances can limit their ability to be breastfed or receive breast
Listeria þþ þ þ
milk. Moreover, they often spend long periods of time in neonatal
Staphylococcus aureus þ þ þþ
intensive care units where they are subject to invasive procedures
Coagulase-negative staphylococci e e þþþ
and exposed to nosocomial infections.4
Enterococcus þ e þþ
Meticillin-resistant S. aureus þ/e e þ
Bacterial and fungal infections
Streptococcus pneumoniae þ þ þ
Neonatal infections account for about 1 million neonatal deaths
Gram-negative
per year globally. The incidence varies between five and 170 per
Escherichia coli þþ þ þþ
1000 live births, and it is more common in low and middle-
Acinetobacter e e þ
income countries. In the UK, Western Europe, the USA and
Enterobacter e e þ
Australasia, the incidence is reported as 2e30 per 1000 live births
Klebsiella þ e þþ
depending on whether only culture-proven episodes are included
Pseudomonas e e þ
or whether probable sepsis is accounted for. The incidence is
Serratia e e þ
highest in very-low-birthweight (VLBW) infants.
Citrobacter e e þ
Most infections in the newborn period occur in the first 24
Haemophilus influenzae þ þ þ
hours of life. Neonatal infections are responsible for increased
Salmonella e þ þ
neonatal mortality, severe neurodevelopmental impairment and
Fungi
increased health costs, although currently accurate estimates of
Candida albicans e e þ
their global burden are not available.
Candida spp. e e þ

þþþ, very common; þþ, common; þ, rare; e, extremely rare. EO, early onset; Early-onset (EO) infections: infections occurring in the first 2e3
LO, late onset. days after birth are classified as early onset; they are mostly
caused by transmission of pathogens from the birth canal during
Table 2

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 FETAL AND NEONATAL INFECTIONS
Signs of early-onset infections
C Smelly liquor
C Low Apgar scores
C Requirement for neonatal resuscitation
C Apnoea or tachypnoea
C Grunting
C Nasal flaring
C Sub- and intercostal recessions
C Temperature instability or hypothermia
C Lethargy
C Reduced tone
C Bulging fontanelle
C Poor feeding
C Seizures
C Skin rash
C Jaundice
C Hypotension and shock
C Umbilical cord flare
C Metabolic acidosis
Table 3
or just before birth. The incidence of EO infections varies from
<1 to 10 per 1000 live births depending on whether culture-
proven infections are included alone or combined with sus-
pected (culture-negative, clinical) infections. The most common
pathogens causing EO infections in high income countries are
group B streptococci (GBS) and Escherichia coli, followed by
Staphylococcus aureus and Listeria monocytogenes (Table 2).
A number of factors at delivery are associated with risk of
acquiring neonatal EO infections: maternal pyrexia, cho-
rioamnionitis, prolonged rupture of the membranes (>18e24
hours), premature rupture of membranes, maternal urinary tract
infections, growth of GBS from a vaginal or rectal swab in the last
trimester of pregnancy, a previous baby with GBS disease or a
twin with GBS. Establishing the presence of these risk factors
needs to be part of the clinical history of every unwell neonate.
Clinical presentation and diagnosis e neonates with EO sepsis
or meningitis present with non-specific signs (Table 3). Isolated
pneumonia is a rare occurrence and needs to be distinguished from
meconium aspiration syndrome, respiratory distress syndrome
and transient tachypnoea of the newborn. Although these signs are
common, other pathologies such as perinatal asphyxia and car-
diac, metabolic, oncological and neurological diseases are
encountered in the neonate and should be considered.
Investigations include full blood count, C-reactive protein
(CRP), electrolytes, liver function tests, clotting screen and blood
cultures. Routine urine samples for the investigation of EO
infection are rarely necessary as the same pathogen is invariably
obtained from blood culture. A lumbar puncture is, however,
essential to diagnose meningitis as the signs are non-specific.
Diagnosis of meningitis has implications for antibiotic choice,
duration and outcome.
A PCR for GBS has been developed, and demonstrated a
higher sensitivity than cultures alone in one study. Similarly, the
use of 16S rDNA PCR for culture-negative samples, especially
CSF, appears promising. However, neither of these tests is
currently used in routine practice.
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A chest X-ray is required if signs of respiratory distress are
prominent.
Treatment e supportive management and antibiotics are the
mainstay of treatment.
The most appropriate empirical antibiotic choice should ac-
count for the common pathogens and their antibiotic suscepti-
bility profiles. Typically, penicillin and an aminoglycoside are
recommended. Antibiotics can then be targeted following the
culture results.
Many well infants are currently given antibiotics because of
maternal risk factors, and algorithms to improve the diagnosis of
EO sepsis are being proposed. In these infants, UK National
Institute for Health and Care Excellence guidelines pragmatically
recommend measuring CRP before starting antibiotics and again
at 24 hours, stopping antibiotics at 36 hours if blood cultures
remain negative and C reactive protein normal.
Prophylaxis e different approaches to prevention of GBS
infection are followed in different countries. In the USA and
many European countries, universal screening policy in which all
pregnant women are tested at 35e37 weeks with a low vaginal/
rectal swab is recommended. All women testing positive for GBS
at the point of screening are offered penicillin during labour to
prevent transmission.
This strategy in the USA has reduced the incidence of neonatal
EO GBS infection from around 1e2 to 0.5 per 1000 live births. In
the UK, where the incidence of GBS is already about 0.5 per 1000
live births, a risk-based approach has been adopted, in which
only women with known risk factors for GBS disease are offered
antibiotic prophylaxis during labour.
Late-onset (LO) neonatal infections: LO infections are those
infections occurring after 48e72 hours of age; they are typically
acquired from nosocomial or community sources. The incidence
of LO infection varies from 20 to 30 per 1000 neonatal admis-
sions, depending on whether culture-proven or suspected in-
fections are included.
In the community, LO infections are mostly caused by GBS, E.
coli and viruses. In the hospital setting, a broader range of
pathogens can cause them (Table 2). Healthcare-associated in-
fections are more common in neonatal intensive care units than
in any other paediatric environment. Preterm infants are at
highest risk of LO infections because of their prolonged exposure
to intensive care and their relative immune deficiencies, as pre-
viously described.
By far the most common organisms causing healthcare-
associated infections are coagulase-negative staphylococci
(CoNS), followed by enterococci, S. aureus, E. coli, Klebsiella and
other Enterobacteriaceae. CoNS infections pose a clinical and
epidemiological dilemma as they are common culture contami-
nants but also often responsible for line infections, particularly in
VLBW infants.
Outbreaks of multiresistant Gram-negative bacteria and
meticillin-resistant S. aureus are feared and increasingly common
events in neonatal intensive care units. They have important
management consequences as they often require the closure of
whole or part of the units for variable amounts of time, often
with implications for the broader neonatal network.
Clinical presentation and diagnosis e signs of LO infections
are typically non-specific and include respiratory distress
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 FETAL AND NEONATAL INFECTIONS
requiring increased respiratory support, temperature instability,
apnoeas and bradycardias, feed intolerance, jaundice, seizures,
metabolic acidosis, tachycardia and hypotension.
As with EO infections, the diagnosis involves baseline labo-
ratory investigations and cultures of blood, urine and CSF. Mo-
lecular techniques are not often used in routine practice.
Lumbar puncture remains essential as the clinical picture does
not discriminate between sepsis and meningitis.
Treatment e optimal management involves both supportive
measures and antimicrobial therapy.
In hospitalized neonates, the choice of empirical antibiotics
depends on the local epidemiology and antimicrobial suscepti-
bilities. In many neonatal units, a combination of flucloxacillin
and an aminoglycoside provides good cover for the most com-
mon pathogens, although amoxicillin may be best where
enterococci are more common than S. aureus. Cephalosporins
used as single agents should be discouraged in this environment
as they induce the spread of extended spectrum b-lactamase
(ESBL) organisms. Third-generation cephalosporins have a role
in the treatment of confirmed bacterial meningitis. Although
CoNS are the most frequent bacteria isolated from blood cultures,
vancomycin use should be restricted to empirical use in high-risk
babies and/or to proven infections. Antibiotic treatment needs to
be targeted when isolates are available.
Neonates admitted from the community are commonly
treated with a third-generation cephalosporin, together with
penicillin to cover for Listeria.
Prophylaxis e given the high incidence and the devastating
effects of neonatal infections in VLBW infants in neonatal units,
several adjuvant therapies and prophylaxis strategies have been
considered.
Several measures have proven invaluable in reducing the rate
of infection, particularly for those that are catheter related. These
include hygiene measures, such as consistent hand-washing, use
of hand gels, bundles of care to improve asepsis in central
venous access insertion and management, cohorting of colonized
or infected neonates, antibiotic stewardship, and the use of sys-
tems that increase standardization and vigilance of infection
control policies, such as the Matching Michigan method.
Antifungal prophylaxis has been shown to reduce the risk of
fungal infections in VLBW infants when given from birth until 6
weeks of age, in units with high prevalence of fungal infections.
Evidence of an increase risk of resistant candida species however
is emerging in units using routine fluconazole prophylaxis. Other
interventions, such as bovine lactoferrin, seem promising but are
still under study. Unfortunately, a number of other measures
such as probiotics, intravenous immunoglobulins and colony-
stimulating factors have not so far proven beneficial in pre-
venting neonatal infections.
Maternal vaccination is becoming an expanding area of
research, and has been demonstrated to be very effective in
protecting young infant from pertussis in the UK. It is possible
that in future new maternal vaccines, such as a GBS vaccine, will
become available.
Viral infections
Respiratory viruses such as rhinoviruses, respiratory syncytial
virus, human metapneumovirus, and influenza, parainfluenza
and bocaviruses, often acquired in the community, can affect all
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ages including neonates. In neonates, the signs of infections are
less well characterized and can mimic those of bacterial sepsis.
Respiratory viruses also have the potential to cause outbreaks in
hospitalized neonates and can have severe consequences,
particularly in preterm infants. Diagnosis is by immunofluores-
cence or PCR on nasopharyngeal aspirate, endotracheal aspirate
or bronchoalveolar lavage. Treatment is supportive.
Enteroviruses and parechoviruses, and less frequently ade-
noviruses and coxsackie viruses can cause severe disease
including encephalitis and meningitis in neonates in both the
community and in neonatal nurseries, with signs that can be
indistinguishable from bacterial infections. Diagnosis is by
appropriate viral immunofluorescence/PCR from multiple spec-
imens such as blood, CSF, nasopharyngeal aspirate/endotracheal
secretions, throat swabs, rectal swabs and stools.
The epidemiology is less well studied than for bacterial in-
fections as PCR techniques are not routinely used. It is likely that
in the future the importance and epidemiology of viral infections
in this age group will be better described.
Herpes simplex virus: neonatal HSV infection is rare but
increasing. If unrecognized, it is lethal in >70% of cases. The
virus is acquired at birth through the vaginal canal. It is more
likely to be transmitted during primary maternal disease (50
e60%), but can also be transmitted during reoccurrences (2%).
Infants typically present between 10 and 21 days with a ve-
sicular rash with an erythematous base on the skin or mucous
membranes. This mostly occurs in excoriated areas. If not
treated, the disease progresses to systemic disease. In about 60%
of cases, the rash is not present.
Neonates can present with central nervous system disease in
their second or third week, with fever and seizures. About one-
third of cases present with a sepsis-like syndrome within the first
10 days. HSV has a characteristic tropism for the liver, causing
deranged liver transaminases, jaundice and clotting abnormal-
ities, or frank disseminated intravascular coagulation. HSV is
diagnosed by a direct fluorescent antibody test from vesicle
material, or from PCR on skin, blood or CSF. Management re-
quires supportive care and intravenous aciclovir for a minimum
of 2e3 weeks, depending on whether meningitis/encephalitis is
confirmed. Treatment is followed by oral aciclovir prophylaxis
for a prolonged period.
In systemic disease, even when appropriately treated, the case
fatality rate is as high as 50%. Meningo-encephalitis is associated
with 15% mortality and severe neurological sequelae in >50% of
cases. The prognosis is good when the infection is limited to the
skin and is appropriately treated.
Pregnant women who acquire primary infection in the third
trimester of pregnancy have the highest risk of vertical trans-
mission; they should be treated with oral aciclovir and offered
elective caesarean section. Their infants are treated with intra-
venous aciclovir prophylaxis.
When a pregnant woman has recurrent disease, the likelihood
of transmission is lower. Spontaneous vaginal delivery is
advised, and extensive swabbing of the infant at 24e48 hours is
recommended in well infants with either prophylactic treatment
with intravenous aciclovir pending results, or a wait and watch
approach in which only symptomatic infants are treated.5 Un-
fortunately, most neonatal herpes infections occur in infants
7 Ó 2017 Published by Elsevier Ltd.
 FETAL AND NEONATAL INFECTIONS

where maternal infection has not been detected in pregnancy,
reducing the impact of prophylaxis protocol.
Varicella zoster virus (VZV): VZV infection in a susceptible
woman in the first 20 weeks of pregnancy is associated with
congenital infection in around 2% of cases (Table 1). However,
when primary varicella infection occurs in the mother between 5
days before and 5 days after delivery, the neonate is at risk of
severe disseminated disease in around 20% of cases. In this sit-
uation, varicella-zoster-specific immunoglobulin needs to be
administered to the baby to prevent or ameliorate subsequent
disease. A 4 Sharma AA, Jen R, Butler A, Lavoie PM. The developing human
KEY REFERENCES
1 Newman L, Kamb M, Hawkes S, et al. Global estimates of syphilis
in pregnancy and associated adverse outcomes: analysis of
multinational antenatal surveillance data. PLoS Med 2013; 10:
e1001396.
2 Kimberlin DW, Jester PM, Sa nchez PJ, et al. for the National
Institute of Allergy and Infectious Diseases Collaborative Antiviral
Study Group. Treatment of symptomatic infection in the neonatal
period has radically changed following a randomised controlled
study comparing 6 weeks versus 6 months treatment with oral
valgancyclovir and demonstrating better neuro-developmental
outcomes at 24 months in the arm treated for 6 months. N Engl J
Med 2015; 372: 933e43.
3 Costello A, Dua T, Duran P, et al. Defining the syndrome associated
with congenital Zika virus infection. Bull World Health Organ 2016;
94. 406e406A.
preterm neonatal immune system: a case for more research in this
area. Clin Immunol 2012; 145: 61e8.
5 Kimberlin DW, Baley J, Committee on Infectious Diseases and
Committee on Fetus and Newborn. Guidance on management of
asymptomatic neonates born to women with active genital herpes
lesions. Pediatrics 2013; 131: e635e46.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 What is the next most appropriate action?

A Examine the baby for other abnormalities
A 20-day-old baby, born at 35 weeks’ gestation, had failed the
B Perform Zika virus serology on the mother
hearing screening on one side. The baby was otherwise well.
C Prepare a genogram on the family
D Perform Toxoplasma serology on the baby
Investigations
E Examine the placenta for signs of insufficiency
Urine testing for cytomegalovirus positive on day 2 and day 20.

What is the next best management step for this baby? Question 3
A. Repeat the hearing test
A 20-day-old baby on the neonatal unit was not tolerating enteral
B. Start intravenous ganciclovir
feeds and had spiking temperatures. She was born at term but
C. Follow-up but no treatment
needed repair of a gastroschisis. Postoperatively, she needed
D. Oral valganciclovir within the neonatal period
parenteral feeding and developed spiking fevers. She had had a
E. Intravenous immunoglobulin
long line in situ for 7 days and had been given 2 days of first-line
late-onset sepsis treatment (flucloxacillin, gentamicin).
Question 2
What is the next best step?
A newborn baby is noticed to have a small head and not to feed
A Add fluconazole
well. The family had recently moved to the area from Brazil and
B Stop all antibiotics
there is no information about the antenatal scans. The mother
C Remove the long line
had been unwell with a flu-like syndrome between the first and
D Broaden the antimicrobial cover
second trimesters of pregnancy, and her cat had a litter of kittens
E Change antibiotics to meropenem
during her pregnancy.

MEDICINE --:- 8 Ó 2017 Published by Elsevier Ltd.

Please cite this article in press as: Vergnano S, Heath PT, Fetal and neonatal infections, Medicine (2017), http://dx.doi.org/10.1016/
j.mpmed.2017.08.011