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Fetal and neonatal infections
FETAL AND NEONATAL INFECTIONS
Fetal and neonatal infections
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 prophylaxis 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 empirical antibiotic choices are made
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 immunocompromised, and prematurity increases the risk of infection. Newborns acquire 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 addresses the most common agents causing congenital and neonatal infections, their clinical manifestations, management and prophylaxis.
Keywords CMV; cross-infection; fetus; GBS; HSV; MRCP; newborn; sepsis; syphilis; Toxoplasma; VZV; Zika
different pathogens: congenital toxoplasmosis is more likely if infection is later in pregnancy (30e75%), while rubella transmission 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.
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. Infections in the first trimester are generally more likely to cause severe defects and can result in stillbirth. Infants can be symptomatic in early life, or symptoms and signs can manifest later in life (Table 1). These protean manifestations depend on the organism, 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 nutrition 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
Clinical manifestations, investigations and management The clinical manifestations of congenital infections are variable. Infection during the early stages of pregnancy severely compromises 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, hepatosplenomegaly, jaundice and intracranial calcifications. Characteristic congenital malformations are described for some infections (Table 1).
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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FETAL AND NEONATAL INFECTIONS
Congenital infections Viruses
Time of acquisition
Maternal immunity
Manifestation at birth
Treatment and prevention
Cytomegalovirus Mostly during third (CMV) trimester
Primary infection > reinfections
Asymptomatic (90%) Blueberry muffin, petechial rash, hepatosplenomegaly, microcephaly, ocular involvement, intracranial calcifications, jaundice, thrombocytopenia, abnormal liver function tests Later development of hearing loss Asymptomatic or lymphadenopathy, hepatosplenomegaly
Oral valganciclovir for 6 months if congenital CMV is diagnosed in the neonatal period and the infant is symptomatic
HIV
Mostly during delivery Risk increases with and breastfeeding high viral load and low CD4 cell count
Hepatitis B
Typically chronic carriage in mother
Zika virus
Unknown
Parvovirus B19
Mostly during the first Primary infection 20 weeks Mostly during the first Primary infection 20 weeks
Varicella-zoster
Bacteria Rubella
Treponema pallidum
Mycobacterium tuberculosis
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Mostly in the first trimester (80%)
Risk of transmission: Asymptomatic HbSAgþ HbeAge: 5 e20% HbSAgþ HbeAgþ: 70 e90% Likely primary Microcephaly, cortical atrophy, brainstem infection abnormality, craniofacial disproportion, seizures, spasticity, cardiac malformations, digestive system malformations
Hydrops fetalis Anaemia Asymptomatic, congenital scarring of the skin, cutaneous defects, bullous lesions, asymmetrical limb hypoplasia and autonomic dysfunction, eye defects, seizures and mental retardation
Primary infection
Asymptomatic, IUGR, thrombocytopenic purpura, hepatosplenomegaly, lymphadenopathy, jaundice, eye involvement, cardiac abnormalities, pneumonitis, meningo-encephalitis, bone lesions, cryptorchidism, haemolytic anaemia Progressive disease in some cases From 14 weeks’ Primary infection 70 Asymptomatic gestation, risk e100% transmission Petechial, vesciculo-bullous or macular rash increases Secondary infection affecting also palms and soles, progressively 40% transmission hepatosplenomegaly, lymphadenopathy, rhinorrhoea, jaundice, anaemia, CSF abnormalities, bone abnormalities on X-ray Rare, transmission can Asymptomatic be in utero and at Miliary tuberculosis delivery
2
Highly active antiretroviral combination therapy in mothers and avoidance of breastfeeding where safe, affordable and sustainable, exclusive breastfeeding if not possible Vaccination at birth if mother HbSAgþ HbeAge Passive and active vaccination at birth if HbSAgþ HbeAgþ Prevention: vaccination Prevention of infection in pregnancy through avoidance of travel to high-risk areas, protection against mosquito bites, avoidance of pregnancy No treatment is available There are case reports of successful intravenous Ig use for treatment Prevention: C Vaccination before pregnancy C Varicella-zoster Ig after exposure
Prevention: vaccination before pregnancy
Parenteral benzylpenicillin for 10 days
Quadruple antimycobacterial therapy
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FETAL AND NEONATAL INFECTIONS
Table 1 (continued ) Viruses Protozoa Toxoplasma
Time of acquisition
Maternal immunity
Manifestation at birth
Treatment and prevention
Highest risk if infection acquired late in pregnancy (5e15% risk in first trimester, 25e40% in second, 30e75% in third)
Mostly primary infection but congenital infections described following reactivations
Asymptomatic to IUGR, hepatosplenomegaly, petechiae, skin rash, pneumonitis, diarrhoea, hypothermia, intracranial and hepatic cranial calcifications, eye involvement, encephalitis with or without seizures, hearing impairment. Triad: chorioretinitis, intracranial calcifications, hydrocephalus
Pyrimethamine and sulfadiazine þ folinic acid Prevention: avoid raw meat and wash hands if any risk of contact with cats’ faeces
Ig, immunoglobulin; IUGR, intrauterine growth restriction; CSF, cerebrospinal fluid.
Table 1
Transmission routes of congenital and neonatal infections Maternal infection Transuterine and birth canal
Haematogenous
Neonatal infection
Fetal/congenital infection First trimester
Second trimester
Breastfeeding
Third trimester
Birth 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
Fetal infection occurs mostly during primary maternal infection, and the risk of transmission increases as pregnancy progress (Figure 1). The degree of fetal compromise is, however, greater in the first trimester and progressively diminishes. Diagnosis during pregnancy is through serology in symptomatic women, or during routine screening. Serology requires careful interpretation, and the toxoplasmosis reference laboratory 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 lesions might progress and require further treatment.
Investigations should be prompted by severe IUGR, intracranial 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 accurate 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 travelling 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 acquired 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 manifestations 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 congenital 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 valganciclovir is effective when started after the neonatal period.
Syphilis Congenital syphilis is a preventable disease; however, it is estimated to cause at least 520,000 adverse fetal outcomes per year globally in terms of stillbirths, early deaths and congenital infections. 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 lumbar 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 unknown antenatal syphilis serology a high index of suspicion
Congenital toxoplasmosis Congenital toxoplasmosis is rare in the UK and North America, with an adult seroprevalence of 10e30%. In Southern and Central 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 pregnancy is undertaken.
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FETAL AND NEONATAL INFECTIONS
needs to be maintained and serology obtained. Point of care testing exist and are widely used in low and middle-income countries. The gold standard antibiotic for treatment is benzylpenicillin, given for 10e14 days. Infected infants should be followed up at regular intervals of 3 months until serology becomes negative. In 2014, the World Health Organization launched a campaign to eliminate congenital syphilis, and this gained some momentum when coupled with prevention of mother to child transmission of HIV (PMTCT) in 2014.
Causality has not been confirmed; however, viral tropism for the CNS demonstrated in animals, isolation of the virus from the CNS of affected fetuses, confirmation of infection in pregnant women carrying infants with microcephaly and epidemiological increase of microcephaly in Brazil at the time of the Zika epidemic all clinically point to Zika as a cause for this congenital syndrome. Zika virus is a flavivirus transmitted by Aedes spp. mosquitoes in tropical, subtropical and temperate areas in more than 80 countries to date. The virus is present in blood and other bodily fluids, including semen. Sexual transmission has been described. A mild viral infection after 4e8 days’ incubation develops in adults, with an itchy rash, non-purulent conjunctivitis, fever, arthralgia and sometimes myalgia and abdominal symptoms. Carriage in semen can persist for prolonged periods, therefore couples travelling to areas at risk needs to be counselled about using effective barrier contraception also on return from the affected areas. The diagnosis of congenital Zika syndrome requires the exclusion of other causes of congenital abnormalities, a suggestive exposure history and confirmation of the virus by molecular diagnosis (PCR) or serology. It is currently not clear when in pregnancy the risk of motherto-child transmission is highest.3
Zika virus An increased number of infants born with microcephaly (<2 SD for age) in association with a Zika virus outbreak in Brazil in 2015, and a similar finding retrospectively identified in the French Polynesia epidemic in 2013e2014, raised the possibility of a causal association between the virus and a new congenital syndrome. Congenital Zika syndrome is associated with craniofacial disproportion, seizures, spasticity and brainstem abnormalities, such as feeding difficulties, vision and hearing defects. An increasing number of brain abnormalities are being reported, such as subcortical calcifications, cortical malformation, retinal abnormalities, cerebral atrophy, neuronal migration defects and ventriculomegaly. Other organs can also be involved, with cardiac and digestive system abnormalities (Table 1).
Infections acquired intrapartum or during the neonatal period Neonates are immunocompromised for many reasons: their skin and mucous membranes are thin and provide a weak barrier to infections, and their immune system is immature with regard to both specific and innate immunity. Neonates born prematurely are at even higher risk of infections as, additionally, they lack protection by maternally derived antibodies. The transplacental passage of maternal IgG occurs mostly in the last trimester of pregnancy, and the acquisition of maternal IgA through breast milk is often not possible because clinical circumstances can limit their ability to be breastfed or receive breast milk. Moreover, they often spend long periods of time in neonatal intensive care units where they are subject to invasive procedures and exposed to nosocomial infections.4
Common bacteria and fungi causing neonatal infections
Gram-positive Group B streptococci Listeria Staphylococcus aureus Coagulase-negative staphylococci Enterococcus Meticillin-resistant S. aureus Streptococcus pneumoniae Gram-negative Escherichia coli Acinetobacter Enterobacter Klebsiella Pseudomonas Serratia Citrobacter Haemophilus influenzae Salmonella Fungi Candida albicans Candida spp.
EO
Community acquired LO
Hospital acquired LO
þþþ þþ þ e þ þ/e þ
þ þ þ e e e þ
þ þ þþ þþþ þþ þ þ
þþ e e þ e e e þ e
þ e e e e e e þ þ
þþ þ þ þþ þ þ þ þ þ
e e
e e
þ þ
Bacterial and fungal infections Neonatal infections account for about 1 million neonatal deaths per year globally. The incidence varies between five and 170 per 1000 live births, and it is more common in low and middleincome countries. In the UK, Western Europe, the USA and Australasia, the incidence is reported as 2e30 per 1000 live births depending on whether only culture-proven episodes are included or whether probable sepsis is accounted for. The incidence is highest in very-low-birthweight (VLBW) infants. Most infections in the newborn period occur in the first 24 hours of life. Neonatal infections are responsible for increased neonatal mortality, severe neurodevelopmental impairment and increased health costs, although currently accurate estimates of their global burden are not available. Early-onset (EO) infections: infections occurring in the first 2e3 days after birth are classified as early onset; they are mostly caused by transmission of pathogens from the birth canal during
þþþ, very common; þþ, common; þ, rare; e, extremely rare. EO, early onset; LO, late onset.
Table 2
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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 account for the common pathogens and their antibiotic susceptibility 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.
Signs of early-onset infections C C C C C C C C C C C C C C C C C C
Smelly liquor Low Apgar scores Requirement for neonatal resuscitation Apnoea or tachypnoea Grunting Nasal flaring Sub- and intercostal recessions Temperature instability or hypothermia Lethargy Reduced tone Bulging fontanelle Poor feeding Seizures Skin rash Jaundice Hypotension and shock Umbilical cord flare 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 cultureproven infections are included alone or combined with suspected (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, chorioamnionitis, 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 cardiac, 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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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 admissions, depending on whether culture-proven or suspected infections 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 infections 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 previously described. By far the most common organisms causing healthcareassociated 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 contaminants 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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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 immunofluorescence or PCR on nasopharyngeal aspirate, endotracheal aspirate or bronchoalveolar lavage. Treatment is supportive. Enteroviruses and parechoviruses, and less frequently adenoviruses 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 specimens such as blood, CSF, nasopharyngeal aspirate/endotracheal secretions, throat swabs, rectal swabs and stools. The epidemiology is less well studied than for bacterial infections 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.
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 laboratory investigations and cultures of blood, urine and CSF. Molecular 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 susceptibilities. In many neonatal units, a combination of flucloxacillin and an aminoglycoside provides good cover for the most common 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 systems 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 colonystimulating factors have not so far proven beneficial in preventing 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.
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 vesicular 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 onethird 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 abnormalities, 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 requires 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 transmission; they should be treated with oral aciclovir and offered elective caesarean section. Their infants are treated with intravenous 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 Unfortunately, most neonatal herpes infections occur in infants
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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nchez PJ, et al. for the National 2 Kimberlin DW, Jester PM, Sa 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. 4 Sharma AA, Jen R, Butler A, Lavoie PM. The developing human 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.
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 situation, varicella-zoster-specific immunoglobulin needs to be administered to the baby to prevent or ameliorate subsequent disease. A 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.
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. What is the next most appropriate action? A Examine the baby for other abnormalities B Perform Zika virus serology on the mother C Prepare a genogram on the family D Perform Toxoplasma serology on the baby E Examine the placenta for signs of insufficiency
Question 1 A 20-day-old baby, born at 35 weeks’ gestation, had failed the hearing screening on one side. The baby was otherwise well. Investigations Urine testing for cytomegalovirus positive on day 2 and day 20. What is the next best management step for this baby? A. Repeat the hearing test B. Start intravenous ganciclovir C. Follow-up but no treatment D. Oral valganciclovir within the neonatal period E. Intravenous immunoglobulin
Question 3 A 20-day-old baby on the neonatal unit was not tolerating enteral feeds and had spiking temperatures. She was born at term but needed repair of a gastroschisis. Postoperatively, she needed parenteral feeding and developed spiking fevers. She had had a 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 Add fluconazole B Stop all antibiotics C Remove the long line D Broaden the antimicrobial cover E Change antibiotics to meropenem
A newborn baby is noticed to have a small head and not to feed well. The family had recently moved to the area from Brazil and there is no information about the antenatal scans. The mother had been unwell with a flu-like syndrome between the first and second trimesters of pregnancy, and her cat had a litter of kittens during her pregnancy.
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Fetal and neonatal infections
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 prophylaxis 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 empirical antibiotic choices are made
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 immunocompromised, and prematurity increases the risk of infection. Newborns acquire 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 addresses the most common agents causing congenital and neonatal infections, their clinical manifestations, management and prophylaxis.
Keywords CMV; cross-infection; fetus; GBS; HSV; MRCP; newborn; sepsis; syphilis; Toxoplasma; VZV; Zika
different pathogens: congenital toxoplasmosis is more likely if infection is later in pregnancy (30e75%), while rubella transmission 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.
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. Infections in the first trimester are generally more likely to cause severe defects and can result in stillbirth. Infants can be symptomatic in early life, or symptoms and signs can manifest later in life (Table 1). These protean manifestations depend on the organism, 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 nutrition 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
Clinical manifestations, investigations and management The clinical manifestations of congenital infections are variable. Infection during the early stages of pregnancy severely compromises 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, hepatosplenomegaly, jaundice and intracranial calcifications. Characteristic congenital malformations are described for some infections (Table 1).
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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FETAL AND NEONATAL INFECTIONS
Congenital infections Viruses
Time of acquisition
Maternal immunity
Manifestation at birth
Treatment and prevention
Cytomegalovirus Mostly during third (CMV) trimester
Primary infection > reinfections
Asymptomatic (90%) Blueberry muffin, petechial rash, hepatosplenomegaly, microcephaly, ocular involvement, intracranial calcifications, jaundice, thrombocytopenia, abnormal liver function tests Later development of hearing loss Asymptomatic or lymphadenopathy, hepatosplenomegaly
Oral valganciclovir for 6 months if congenital CMV is diagnosed in the neonatal period and the infant is symptomatic
HIV
Mostly during delivery Risk increases with and breastfeeding high viral load and low CD4 cell count
Hepatitis B
Typically chronic carriage in mother
Zika virus
Unknown
Parvovirus B19
Mostly during the first Primary infection 20 weeks Mostly during the first Primary infection 20 weeks
Varicella-zoster
Bacteria Rubella
Treponema pallidum
Mycobacterium tuberculosis
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Mostly in the first trimester (80%)
Risk of transmission: Asymptomatic HbSAgþ HbeAge: 5 e20% HbSAgþ HbeAgþ: 70 e90% Likely primary Microcephaly, cortical atrophy, brainstem infection abnormality, craniofacial disproportion, seizures, spasticity, cardiac malformations, digestive system malformations
Hydrops fetalis Anaemia Asymptomatic, congenital scarring of the skin, cutaneous defects, bullous lesions, asymmetrical limb hypoplasia and autonomic dysfunction, eye defects, seizures and mental retardation
Primary infection
Asymptomatic, IUGR, thrombocytopenic purpura, hepatosplenomegaly, lymphadenopathy, jaundice, eye involvement, cardiac abnormalities, pneumonitis, meningo-encephalitis, bone lesions, cryptorchidism, haemolytic anaemia Progressive disease in some cases From 14 weeks’ Primary infection 70 Asymptomatic gestation, risk e100% transmission Petechial, vesciculo-bullous or macular rash increases Secondary infection affecting also palms and soles, progressively 40% transmission hepatosplenomegaly, lymphadenopathy, rhinorrhoea, jaundice, anaemia, CSF abnormalities, bone abnormalities on X-ray Rare, transmission can Asymptomatic be in utero and at Miliary tuberculosis delivery
2
Highly active antiretroviral combination therapy in mothers and avoidance of breastfeeding where safe, affordable and sustainable, exclusive breastfeeding if not possible Vaccination at birth if mother HbSAgþ HbeAge Passive and active vaccination at birth if HbSAgþ HbeAgþ Prevention: vaccination Prevention of infection in pregnancy through avoidance of travel to high-risk areas, protection against mosquito bites, avoidance of pregnancy No treatment is available There are case reports of successful intravenous Ig use for treatment Prevention: C Vaccination before pregnancy C Varicella-zoster Ig after exposure
Prevention: vaccination before pregnancy
Parenteral benzylpenicillin for 10 days
Quadruple antimycobacterial therapy
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Table 1 (continued ) Viruses Protozoa Toxoplasma
Time of acquisition
Maternal immunity
Manifestation at birth
Treatment and prevention
Highest risk if infection acquired late in pregnancy (5e15% risk in first trimester, 25e40% in second, 30e75% in third)
Mostly primary infection but congenital infections described following reactivations
Asymptomatic to IUGR, hepatosplenomegaly, petechiae, skin rash, pneumonitis, diarrhoea, hypothermia, intracranial and hepatic cranial calcifications, eye involvement, encephalitis with or without seizures, hearing impairment. Triad: chorioretinitis, intracranial calcifications, hydrocephalus
Pyrimethamine and sulfadiazine þ folinic acid Prevention: avoid raw meat and wash hands if any risk of contact with cats’ faeces
Ig, immunoglobulin; IUGR, intrauterine growth restriction; CSF, cerebrospinal fluid.
Table 1
Transmission routes of congenital and neonatal infections Maternal infection Transuterine and birth canal
Haematogenous
Neonatal infection
Fetal/congenital infection First trimester
Second trimester
Breastfeeding
Third trimester
Birth 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 infection occurs mostly during primary maternal infection, and the risk of transmission increases as pregnancy progress (Figure 1). The degree of fetal compromise is, however, greater in the first trimester and progressively diminishes. Diagnosis during pregnancy is through serology in symptomatic women, or during routine screening. Serology requires careful interpretation, and the toxoplasmosis reference laboratory 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 lesions might progress and require further treatment.
Investigations should be prompted by severe IUGR, intracranial 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 accurate 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 travelling 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 acquired 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 manifestations 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 congenital 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 valganciclovir is effective when started after the neonatal period.
Syphilis Congenital syphilis is a preventable disease; however, it is estimated to cause at least 520,000 adverse fetal outcomes per year globally in terms of stillbirths, early deaths and congenital infections. 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 lumbar 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 unknown antenatal syphilis serology a high index of suspicion
Congenital toxoplasmosis Congenital toxoplasmosis is rare in the UK and North America, with an adult seroprevalence of 10e30%. In Southern and Central 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 pregnancy is undertaken.
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needs to be maintained and serology obtained. Point of care testing exist and are widely used in low and middle-income countries. The gold standard antibiotic for treatment is benzylpenicillin, given for 10e14 days. Infected infants should be followed up at regular intervals of 3 months until serology becomes negative. In 2014, the World Health Organization launched a campaign to eliminate congenital syphilis, and this gained some momentum when coupled with prevention of mother to child transmission of HIV (PMTCT) in 2014.
Causality has not been confirmed; however, viral tropism for the CNS demonstrated in animals, isolation of the virus from the CNS of affected fetuses, confirmation of infection in pregnant women carrying infants with microcephaly and epidemiological increase of microcephaly in Brazil at the time of the Zika epidemic all clinically point to Zika as a cause for this congenital syndrome. Zika virus is a flavivirus transmitted by Aedes spp. mosquitoes in tropical, subtropical and temperate areas in more than 80 countries to date. The virus is present in blood and other bodily fluids, including semen. Sexual transmission has been described. A mild viral infection after 4e8 days’ incubation develops in adults, with an itchy rash, non-purulent conjunctivitis, fever, arthralgia and sometimes myalgia and abdominal symptoms. Carriage in semen can persist for prolonged periods, therefore couples travelling to areas at risk needs to be counselled about using effective barrier contraception also on return from the affected areas. The diagnosis of congenital Zika syndrome requires the exclusion of other causes of congenital abnormalities, a suggestive exposure history and confirmation of the virus by molecular diagnosis (PCR) or serology. It is currently not clear when in pregnancy the risk of motherto-child transmission is highest.3
Zika virus An increased number of infants born with microcephaly (<2 SD for age) in association with a Zika virus outbreak in Brazil in 2015, and a similar finding retrospectively identified in the French Polynesia epidemic in 2013e2014, raised the possibility of a causal association between the virus and a new congenital syndrome. Congenital Zika syndrome is associated with craniofacial disproportion, seizures, spasticity and brainstem abnormalities, such as feeding difficulties, vision and hearing defects. An increasing number of brain abnormalities are being reported, such as subcortical calcifications, cortical malformation, retinal abnormalities, cerebral atrophy, neuronal migration defects and ventriculomegaly. Other organs can also be involved, with cardiac and digestive system abnormalities (Table 1).
Infections acquired intrapartum or during the neonatal period Neonates are immunocompromised for many reasons: their skin and mucous membranes are thin and provide a weak barrier to infections, and their immune system is immature with regard to both specific and innate immunity. Neonates born prematurely are at even higher risk of infections as, additionally, they lack protection by maternally derived antibodies. The transplacental passage of maternal IgG occurs mostly in the last trimester of pregnancy, and the acquisition of maternal IgA through breast milk is often not possible because clinical circumstances can limit their ability to be breastfed or receive breast milk. Moreover, they often spend long periods of time in neonatal intensive care units where they are subject to invasive procedures and exposed to nosocomial infections.4
Common bacteria and fungi causing neonatal infections
Gram-positive Group B streptococci Listeria Staphylococcus aureus Coagulase-negative staphylococci Enterococcus Meticillin-resistant S. aureus Streptococcus pneumoniae Gram-negative Escherichia coli Acinetobacter Enterobacter Klebsiella Pseudomonas Serratia Citrobacter Haemophilus influenzae Salmonella Fungi Candida albicans Candida spp.
EO
Community acquired LO
Hospital acquired LO
þþþ þþ þ e þ þ/e þ
þ þ þ e e e þ
þ þ þþ þþþ þþ þ þ
þþ e e þ e e e þ e
þ e e e e e e þ þ
þþ þ þ þþ þ þ þ þ þ
e e
e e
þ þ
Bacterial and fungal infections Neonatal infections account for about 1 million neonatal deaths per year globally. The incidence varies between five and 170 per 1000 live births, and it is more common in low and middleincome countries. In the UK, Western Europe, the USA and Australasia, the incidence is reported as 2e30 per 1000 live births depending on whether only culture-proven episodes are included or whether probable sepsis is accounted for. The incidence is highest in very-low-birthweight (VLBW) infants. Most infections in the newborn period occur in the first 24 hours of life. Neonatal infections are responsible for increased neonatal mortality, severe neurodevelopmental impairment and increased health costs, although currently accurate estimates of their global burden are not available. Early-onset (EO) infections: infections occurring in the first 2e3 days after birth are classified as early onset; they are mostly caused by transmission of pathogens from the birth canal during
þþþ, very common; þþ, common; þ, rare; e, extremely rare. EO, early onset; LO, late onset.
Table 2
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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 account for the common pathogens and their antibiotic susceptibility 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.
Signs of early-onset infections C C C C C C C C C C C C C C C C C C
Smelly liquor Low Apgar scores Requirement for neonatal resuscitation Apnoea or tachypnoea Grunting Nasal flaring Sub- and intercostal recessions Temperature instability or hypothermia Lethargy Reduced tone Bulging fontanelle Poor feeding Seizures Skin rash Jaundice Hypotension and shock Umbilical cord flare 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 cultureproven infections are included alone or combined with suspected (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, chorioamnionitis, 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 cardiac, 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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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 admissions, depending on whether culture-proven or suspected infections 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 infections 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 previously described. By far the most common organisms causing healthcareassociated 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 contaminants 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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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 immunofluorescence or PCR on nasopharyngeal aspirate, endotracheal aspirate or bronchoalveolar lavage. Treatment is supportive. Enteroviruses and parechoviruses, and less frequently adenoviruses 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 specimens such as blood, CSF, nasopharyngeal aspirate/endotracheal secretions, throat swabs, rectal swabs and stools. The epidemiology is less well studied than for bacterial infections 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.
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 laboratory investigations and cultures of blood, urine and CSF. Molecular 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 susceptibilities. In many neonatal units, a combination of flucloxacillin and an aminoglycoside provides good cover for the most common 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 systems 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 colonystimulating factors have not so far proven beneficial in preventing 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.
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 vesicular 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 onethird 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 abnormalities, 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 requires 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 transmission; they should be treated with oral aciclovir and offered elective caesarean section. Their infants are treated with intravenous 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 Unfortunately, most neonatal herpes infections occur in infants
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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FETAL AND NEONATAL INFECTIONS
nchez PJ, et al. for the National 2 Kimberlin DW, Jester PM, Sa 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. 4 Sharma AA, Jen R, Butler A, Lavoie PM. The developing human 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.
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 situation, varicella-zoster-specific immunoglobulin needs to be administered to the baby to prevent or ameliorate subsequent disease. A 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.
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. What is the next most appropriate action? A Examine the baby for other abnormalities B Perform Zika virus serology on the mother C Prepare a genogram on the family D Perform Toxoplasma serology on the baby E Examine the placenta for signs of insufficiency
Question 1 A 20-day-old baby, born at 35 weeks’ gestation, had failed the hearing screening on one side. The baby was otherwise well. Investigations Urine testing for cytomegalovirus positive on day 2 and day 20. What is the next best management step for this baby? A. Repeat the hearing test B. Start intravenous ganciclovir C. Follow-up but no treatment D. Oral valganciclovir within the neonatal period E. Intravenous immunoglobulin
Question 3 A 20-day-old baby on the neonatal unit was not tolerating enteral feeds and had spiking temperatures. She was born at term but needed repair of a gastroschisis. Postoperatively, she needed parenteral feeding and developed spiking fevers. She had had a 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 Add fluconazole B Stop all antibiotics C Remove the long line D Broaden the antimicrobial cover E Change antibiotics to meropenem
A newborn baby is noticed to have a small head and not to feed well. The family had recently moved to the area from Brazil and there is no information about the antenatal scans. The mother had been unwell with a flu-like syndrome between the first and second trimesters of pregnancy, and her cat had a litter of kittens during her pregnancy.
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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