Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015–16 Lancet Infect Dis 2017
outbreak of Zika virus and congenital Zika infection brought the world’s attention to links between Zika infection and Published Online
microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in August 22, 2017
http://dx.doi.org/10.101
which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital
6S1473-3099(17)30398-5
infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis,
Institute for Global Health,
management, and long-term consequences of these infections. We include infections that cause substantial impairment: University College London,
cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues London, UK (D Devakumar PhD,
with classification of microcephaly and show how some infants affected by congenital infection might be missed or Prof I Abubakar PhD); Infectious
Diseases Department, Great
incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly,
Ormond Street Hospital,
prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important London, UK (A Bamford PhD);
global public health priorities. Department of Parasitology,
Institute for Biomedical
Introduction head circumference more than 2 SDs below the median Sciences (Prof M U Ferreira PhD)
and Department of Nutrition,
The recent outbreak of microcephaly associated with (<–2 Z scores) for gestational age and sex in an School of Public Health
congenital Zika virus infection, first identified in Latin appropriate healthy reference population, with severe (Prof M A Cardoso PhD),
America, has drawn attention to Zika virus because the microcephaly defined as lower than –3 Z scores.3–5 The University of São Paulo,
São Paulo, Brazil; Great
outbreak led to previously unknown congenital reference range and population from which a definition
Ormond Street Institute of
microcephaly in a susceptible population, which affected is taken can vary, for example country-specific ranges, Child Health, University College
a very large number of infants.1,2 However, Zika virus is WHO child-growth ranges for full-term infants, the London, London, UK
part of a group of infectious diseases that can be Fenton ranges for preterm infants, and the InterGrowth (R E Rosch BMBCh,
Prof A J Copp DPhil,
transmitted to the fetus and cause microcephaly, and reference ranges are all used.6 This inconsistency limits
P Alexandre PhD, A Bamford);
microcephaly is likely to represent the most noticeable the comparability of microcephaly prevalence estimates Department of Paediatrics,
feature in terms of developmental abnormalities, forming and accounts for a proportion of the global variability in University of Oxford, Oxford,
part of a syndrome for each infection. Understanding the rates. WHO currently recommends the Intergrowth 21st UK (J Broad MBChB); Leonard
Cheshire Disability and
different infectious causes of microcephaly will help criteria if the gestational age is known and WHO Child Inclusive Development Centre,
clinicians, researchers, and policy makers contextualise Growth Standards if it is not.3,7,8 Furthermore, and University College London,
the recent microcephaly outbreak and can be applied to probably more importantly, inconsistency in frequency London, UK (Prof N Groce PhD);
help the individual child and inform appropriate planning and rigour of measurement, and completeness of Division of Infection and
Immunity, University College
of services for the population. reporting, makes population prevalences difficult to London, London, UK
In this Review, we examine the major congenital ascertain. A study9 done across Europe found a prevalence, (Prof J Breuer MD); and
infections that can cause microcephaly, focusing on those excluding genetic conditions, of 1·53 (95% CI 1·16–1·96) Department of Infectious
with the largest disease burden and the strongest evidence per 10 000 births (including livebirths, fetal deaths from Disease Epidemiology, London
School of Hygiene & Tropical
for causation: cytomegalovirus, herpes simplex virus 20 weeks’ gestation, and termination of pregnancy for Medicine, London, UK
(HSV), rubella virus, Toxoplasma gondii, and Zika virus. fetal anomaly). Inclusion of genetic conditions would (Prof L C Rodrigues PhD)
We describe the epidemiology, pathogenesis, transmission, increase the prevalence to approximately 2·0 per 10 000 Correspondence to:
clinical features, management, and long-term disability in births. There was considerable variation in the estimates, Dr Delan Devakumar, Institute
childhood. Less frequent causes of primary microcephaly from 0·41 per 10 000 births in Portugal to 4·25 per 10 000 for Global Health, University
College London,
are not considered in this Review. Although congenital births in the UK, and in the definition of microcephaly London WC1N 1EH, UK
syphilis has a high disease burden in regions affected by (<–2 Z scores, <–3 Z scores, and clinical decisions), the d.devakumar@ucl.ac.uk
Zika virus, and varicella zoster virus has recognised reference ranges used, and methods of ascertainment.9
neurotropic properties, published reports describing Microcephaly can be divided into two types: primary,
primary microcephaly in the context of these two infections which develops before 32 weeks of gestation10 or birth,11
are scarce. and secondary, which develops after these points.
Primary microcephaly, the focus of this Review, is
Microcephaly generally due to disturbed neurogenesis (mitosis or
Microcephaly is a clinical diagnosis made at or after birth progenitor cell function) or death of neuronal
that describes a small head. This diagnosis does not progenitors.11,12 Secondary microcephaly normally relates
necessarily indicate abnormal brain development, and to the postnatal development and maturation of neurons
some children with microcephaly are healthy. An (dendritic processes and synaptic connections).10
accepted definition of microcephaly is occipitofrontal Infection can lead to both primary or secondary
A B
200 Affected children
Unaffected children
150
Frequency
100
50
0
–6 –5 –4 –3 –2 –1 0 1 2 3 4 5 6 –6 –5 –4 –3 –2 –1 0 1 2 3 4 5 6
Z score Z score
Figure 1: Modelled population effects of insults to brain development on occipitofrontal head circumference
Continuous lines represent the reference population (no children affected), with a mean of 0 and SD of 1. Simulated populations were created using R language and
environment for statistical computing. If an otherwise normal population of 1000 infants (in which children’s occipitofrontal circumferences are close to their expected
values) is exposed to a congenital infection that limits brain development, a proportion of children are labelled as normal by being above the –2 Z scores or –3 Z scores
cutoffs but they might deviate from their expected occipitofrontal head circumference. (A) Congenital infection with a uniform shift to the left by 1 SD relative to the
reference curve in 30% (randomly chosen) of affected children, roughly as expected in congenital toxoplasmosis acquired late in pregnancy. The remaining 70% of
children were not affected at all. In this hypothetical scenario, 6·5% of children fall below the –2 Z score cutoff value for microcephaly, and 0·9% of children fall below
the –3 Z scores. Only 65 (22%) of 300 affected children will actually be classified as microcephalic by using the –2 Z score cutoff. Only children whose ideal occipitofrontal
head circumference would be less than –1 SD of the expected mean (expected proportion of 15·9% in a healthy population), would actually be diagnosed as
microcephalic after the 1 SD shift caused by the infection. (B) Congenital infection where occipitofrontal head circumference is shifted to the left by 2 SD in 10% of
children, roughly as expected for congenital toxoplasmosis acquired early in pregnancy. In this hypothetical scenario, 6·5% of children fall below the –2 Z score cutoff
value for microcephaly; and 1·4% below the –3 Z scores. Here, 65% of affected children will fall below the cutoff value of –2 SD. By counting the number of children
below a given cutoff value we are severely underestimating the proportion of children who have been relatively mildly affected (scenario A) and also that of children
who have been more severely affected (scenario B). Moreover, although (A) and (B) represent conditions varying in severity which affect different proportions of
children in the population, in both examples the prevalence of microcephaly, estimated by applying the –2 Z score cutoff, would be quite similar (around 6·5%).
microcephaly, but this differentiation is often not with normal brain imaging does not necessarily mean
possible if the appropriate head circumference impaired brain growth, a reduction in skull volume is
measurements are not taken. In high-income countries, indicative of underlying cerebral cortical volume loss.10,18
microcephaly is predominantly due to non-infectious A study19 of Finnish full-term infants showed that a
causes,13,14 including genetic abnormalities, nutritional small head circumference at birth was associated with
deficiencies, hypothyroidism, brain injury, alcohol, poorer cognitive scores across multiple domains at
drugs, and placental insufficiency.10,11 A multicentre 56 months.
retrospective analysis14 from Germany found that only If microcephaly is used to screen for congenital
25 (6%) of 403 cases of microcephaly (for which a cause diseases, and if occipitofrontal head circumference is
was identified) were due to maternal infections in normally distributed in the reference population,
pregnancy. The prevalence of in-utero or perinatal 2·3% of the population will be classified as having
infections in cases of severe microcephaly is higher, for microcephaly, many of whom will be healthy. Conversely,
example 46 (16%) of 284 cases in New York, NY, USA, in many neonates with congenital infections that affect the
2013–15.15 brain will not have severe enough manifestations to
A reduction in head size might be associated with cause microcephaly. To illustrate this, we simulate two
intrauterine growth restriction, for example with scenarios (figure 1). A definition of smaller than
cytomegalovirus and Zika virus. Head size can be either –3 Z scores (0·1% of the population)20,21 is expected to be
symmetrically or asymmetrically reduced in relation to 99·9% specific, although much less sensitive (57%).6 An
the overall anthropometry of the infant. The gestation assessment16 of 1501 cases of suspected microcephaly
at which an insult occurs will determine when reported to the Brazilian notification system showed that
microcephaly is clinically detectable. An infection close 21·7% of notified cases classified as definite or probable
to birth might result in brain damage, but with a had a normal head circumference (>–2 Z scores) and
normal head circumference. Microcephaly screening this cutoff had a sensitivity of 83% and specificity of
might be poorly sensitive for infants severely affected 98%. Although screening for microcephaly is a good
by congenital Zika virus infection, particularly as this diagnostic for brain damage caused by a congenital
consists of many other manifestations.16 Clinically infection, some microcephaly cases will appear normal
apparent microcephaly is one of many fetal brain and neurological damage might not be identified.
abnormalities that can lead to later neurodevelopmental Further tools should therefore be used (see Clinical
sequelae.17 Although a clinical diagnosis of microcephaly presentation at birth).
Description Transmission Risk period for transmission Maternal signs and symptoms Prevention of infection and
of infection to the fetus treatment of pregnant women
Cyto β herpes DNA virus; Infectious body fluid (saliva, urine, breast Risk increases with Mostly asymptomatic or influenza- Treatment with antiviral medication
megalovirus Herpesviridae family milk, genital secretions, blood transfusion) gestational age, but early like symptoms not recommended outside trial
infection is associated with settings; candidate vaccines in
severe congenital infection development; hyperimmune globulin
has been trialled but has not been
shown to reduce transmission of
cytomegalovirus to the fetus29
Herpes α herpes DNA Orogenital, genital–genital, transmitted Risk associated Primary genital herpes infection Risk of perinatal transmission can be
simplex viruses; during delivery through infected maternal predominantly with primary might be asymptomatic but is often reduced by caesarean section in the
virus 1 and 2 Herpesviridae family genital tract; virus shed with or without infection late in pregnancy associated with mucocutaneous context of active genital lesions and
lesions present lesions;30 latent infection is suppressive aciclovir or valaciclovir
subsequently established in dorsal given to the mother before delivery32
root ganglia; mucocutaneous lesions
can then recur following viral
reactivation31
Rubella Single stranded RNA Respiratory transmission; human beings Risk of congenital disease in Typically a mild self-limiting illness: Immunisation of girls to prevent
virus virus; Togaviridae are the only known host of rubella33 first 20 weeks; infection maculopapular rash, individual cases and the whole
family beyond this not associated lymphadenopathy, malaise, population to interrupt transmission;
with congenital defects; arthralgia, fever33 supportive management of the
primary maternal infection is infection
associated with up to a 50%
risk of fetal infection34
Toxoplasma Obligate People acquire infection mainly by Risk of congenital Most acute T gondii infections in Treatment of maternal toxoplasmosis
gondii intracellular consumption of raw or undercooked meat transmission increases with immunocompetent pregnant diagnosed through prenatal screening
protozoan parasite containing cysts, by ingesting water or raw gestational age at maternal women are subclinical; fever, with spiramycin or pyrimethamine is
vegetables contaminated with oocysts, or infection: 15% (95% CI lymphadenopathy, and an believed to reduce the risk of mother-
by transplacental transfer of tachyzoites 13–17) at 13 weeks and influenza-like illness are the most to-child transmission and neurological
during an acute infection; tachyzoites 71% (66–76) at 36 weeks36 common clinical signs and sequelae in the fetus in settings where
invade host cells, multiply, and disseminate, symptoms35 low-virulence type II strains
infecting multiple sites in the body predominate, but this protective effect
including brain, eye, heart, skeletal muscle, remains to be confirmed against more
and placenta;35 toxoplasmosis reactivation virulent atypical recombinant strains37
in immunocompromised women might
rarely be a cause; blood transfusion or organ
transplantation; the only definitive hosts
are members of the cat family35
Zika virus Single stranded RNA The main vector is the aedes mosquito. Risk of transmission appears Infection is often asymptomatic in Primary prevention of mosquito
(much arbovirus; Aedes aegypti is considered of greatest to be throughout pregnancy adults, with symptoms reported in bites; no treatment yet
knowledge Flaviviridae family; global importance; also sexual
38
approximately 20% of cases; 40
still there are currently transmission and potentially through common features include pruritic,
provisional) two major lineages: infected blood transfusions;39 non-human maculopapular rash, low grade fever,
one African (with hosts are thought mainly to include arthritis or arthralgia, conjunctivitis,
two groups, the non-human primates, although evidence myalgia, and headache; Zika has
Uganda cluster and of infection has also been demonstrated in been associated with Guillain-Barré
the Nigeria cluster) other mammals38 syndrome, myelitis, and
and one Asian/ meningoencephalitis reported in
American adults41
human beings. Indirect evidence shows that rubella later subventricular zone) are indeed the commonest
infection can slow the rate of cell division, although this brain cell type infected by Zika virus (brain organoids54,55
has not been confirmed in human neural cells in and neurospheres).58 The exposure of these 3D cell
culture.43 cultures to the virus mimics many features of
microcephaly in human beings, including a decrease in
Zika virus neuronal production, reduced ventricular zone
Congenital viral infections and brain development thickness, and overall smaller organoids.55,56,68 This
studies have benefited from recent advances in the reduction in growth seems to result from cell cycle
growth of human cells in 3-dimensional (3D) culture. arrest69 or an increase in cell death,56,58,68,69 and could
Cell aggregates called neurospheres are formed initially, indeed explain the microcephaly phenotype observed in
but with continued and specialised culture they can Zika virus-infected human fetuses. Entry of Zika virus
form organoids that mimic some features of true into neural progenitors has been suggested to occur via
organs. Studies that use these techniques have viral receptor AXL, which mediates Zika virus and
confirmed that neural progenitors (ventricular zone and dengue virus entry into human skin cells,70 and is
strongly expressed in ventricular zone and subventricular giving birth to infected newborns, compared with 65% of
zone neural progenitors.71,72 However, a study73 using mothers who are infected in the third trimester.86 Rates of
human brain organoids revealed that genetic ablation of transmission in non-primary infection are not known but
AXL alone is unable to prevent Zika virus infection, are generally reported to be lower than are those for
suggesting other cell adhesion or entry factors might be primary infections.78,87,88 The risk of congenital cyto
involved. Human fetal organotypic slice culture studies megalovirus infection is increased by maternal HIV
reveal that phospho-TANK binding kinase 1, relocates infection, both for HIV-exposed uninfected and HIV-
from centrosomes to mitochondria following Zika virus infected infants.78 In-utero HIV transmission is particularly
infection, producing mitotic defects and supernumerary associated with congenital cytomegalovirus.89
centrosomes that might exacerbate cell death.72,74
Injection of Zika virus into pregnant macaques and HSV
mice, or into the mouse brain, has confirmed some of Primary microcephaly is a relatively rare complication of
the observations from human in-vitro culture perinatal HSV infection and is mainly found in association
systems.75–77 Dang and colleagues55 also discovered that with in-utero infection, which accounts for only 5% of
Zika virus infection activates TLR3 (involved in cases.30 Global average seroprevalence is 18% among
activation of an immune response), and TLR3 inhibition women of childbearing age, but this figure includes huge
can attenuate apoptosis and decrease growth induced by variations, from 4·1% in Japan, to 62% in east Asia, to 70%
viral infection. Comparison of transcriptome profiles in sub-Saharan Africa.90,91 Neonatal infection at the time of
derived from infected and non-infected animal tissue birth from mothers with symptomatic genital infection is
also highlights new potential molecular viral targets. more common than in-utero infection, but does not cause
These targets include downregulated expression of an primary microcephaly.
extensive list of genes (some centrosome-related)
previously associated with autosomal recessive primary Rubella virus
microcephaly (ASPM, CENPF, MCPH1, STIL, Rubella is a vaccine-preventable disease and rates of
CEP135).75,76 This observation suggests that the infection are largely dependent on the coverage
underlying pathogenesis of autosomal recessive and of immunisation programmes. The global incidence of
virally induced microcephalies might be similar, congenital rubella syndrome has reduced from 0·1–0·2
although this is yet to be confirmed. per 1000 livebirths prior to vaccination to near elimination
(<0·01 per 100 000 livebirths) in areas with comprehensive
Infection in pregnancy vaccination rates.92 Vaccination programmes were
Table 1 describes the epidemiology and clinical features widespread in most countries in 2014, except in sub-
of the main infections associated with microcephaly in Saharan Africa and south Asia.93 Despite widespread
pregnant women. vaccination programmes, an estimated 9·4% of pregnant
women remain seronegative worldwide and therefore
Cytomegalovirus susceptible to infection.94 In areas without vaccination
Most women of childbearing age in low-income and programmes, incidence of congenital rubella syndrome
middle-income countries have long-lasting immunity has been estimated at 19–283 per 100 000 livebirths in the
from prior cytomegalovirus infection, but viral reactivation African region, and 18–309 per 100 000 livebirths in the
can take place in pregnancy or during periods of south Asian region.92
immunosuppression. In sub-Saharan Africa, Latin
America, and south Asia, more than 90% of the general T gondii
population have IgG antibodies, compared with a sero Most women of childbearing age in Latin America
prevalence of 40–60% in high-income countries.78–83 (51–72%), central Europe (58%), and west Africa (54–77%)
Prevalence of congenital cytomegalovirus infection in have specific IgG antibodies to T gondii.95 Conversely,
high-income countries is estimated to be 0·7% of all relatively few women of childbearing age are found to be
livebirths, or 1–5% in low-income countries.78,81,84 seropositive in southeast Asia, China, and South Korea
The risk of in-utero transmission varies according to (4–39%), Scandinavia (11–28%), and the USA (15%).95,96
whether maternal cytomegalovirus infection is primary, a Mother-to-child transmission predominantly occurs
reactivation of latent infection, or superinfection with following primary infection during pregnancy. The
another cytomegalovirus strain.78 Primary infection has the global incidence of congenital toxoplasmosis is estimated
highest risk of in-utero transmission and fetal disease is at 1·5 cases per 1000 livebirths (95% credible interval
most severe, particularly when it occurs early in pregnancy. 1·4–1·6), with the highest incidence in some Latin
Overall, most cases of congenital cytomegalovirus infection American countries (3·4 per 1000 livebirths) and lowest
result from non-primary maternal infection, but most of incidence in parts of Europe (0·5 per 1000 livebirths).97
these infections are asymptomatic.85 Risk of transmission The risk of congenital infection might rise because of
increases with advancing gestational age, with 35% of reactivation of T gondii during immunosuppression, for
mothers who have a primary infection in the first trimester example resulting from HIV.98
Zika virus levels of IgG antibodies might also be present during the
Zika virus has been described for more than 60 years, acute phase of infection.110
with intermittent case reports until outbreaks in Yap In general, detection of cytomegalovirus IgM has been
Island (estimated 73% of the population infected, 95% CI shown to have insufficient sensitivity and specificity,
68–77) in 2007, French Polynesia (up to 66% IgG positive) especially in conditions of immune dysfunction. A
in 2013, and Brazil in 2015.70,99,100 At present, Zika virus positive cytomegalovirus IgM is associated with primary
has been documented in 84 countries or subregional infection in only 10% of cases. ELISA-based IgG avidity
areas and 31 countries have reported microcephaly or tests are widely recommended to distinguish between
neurological malformations associated with Zika virus.101 acute and chronic infections; low-avidity antibodies are
The prevalence of suspected Zika virus disease in women typically found over the first weeks, while high-avidity
of childbearing age is 5400 per 100 000 in Brazil.102 IgG predominates in the chronic phase.107
IgM and IgG antibody tests for dengue virus, West
Laboratory diagnosis during pregnancy Nile fever, and Zika virus, all members of the Flaviviridae
Any pregnant woman presenting with fever or rash family, share considerable epitope cross-reactivity.
should be evaluated for risk of infections that are Plaque reduction neutralising tests can be used to
potentially transmittable to the fetus. There are many differentiate closely related viruses but are too complex
infectious causes of rash, for example parvovirus B19, for routine diagnosis, especially in non-specialised
measles, and varicella zoster, and extensive guidelines laboratories.
exist that describe when testing should be done.103
During the acute infection, laboratory confirmation is In-utero testing
usually only possible where clinical symptoms are When acute maternal infection with any of the previously
present in the mother. Primary cytomegalovirus, HSV, mentioned pathogens is considered to pose a risk,
T gondii, and Zika virus infections might be asymptomatic infection of the infant can be investigated where possible
and therefore the opportunity to confirm acute infection by amplification of pathogen nucleic acid from amniotic
can be missed.104 In acute symptomatic maternal fluid. Amniotic fluid samples are typically obtained at
infection, Zika virus and rubella can be detected in 18 weeks’ gestation to determine fetal infection with
serum, blood, oral fluid, or urine by PCR amplification of T gondii and guide therapy.111 In cytomegalovirus
nucleic acid, and might precede the development of infection, a 6–8 week window exists between maternal
IgM antibodies. Acute primary maternal HSV can be infection and detection of virus in amniotic fluid.
diagnosed by viral PCR and the presence of IgM anti PCR has high sensitivity when performed at the correct
bodies, but usually only when oral or genital lesions are time (20–21 weeks’ gestation or 7 weeks after maternal
present. Virus can be detected for up 10 weeks in serum infection) and, when combined with culture, nearly all
following acute Zika virus infection44 and 2 weeks congenital infections can be diagnosed.78 PCR testing of
following acute rubella infection,105 and cytomegalovirus amniotic fluid for HSV is possible but does not seem to
and HSV are frequently shed asymptomatically from correlate with neonatal infection.112 PCR testing has been
mucosal epithelia.106,107 Detection of T gondii IgA is the shown to be possible with Zika virus.123
most sensitive indicator of congenital infection in the
child.108 Cytomegalovirus shedding in oral fluid might Screening
occur, both during primary infection and asymptomatic Childhood immunisation programmes against rubella
reactivation, and is therefore not always a reliable are routinely available in 147 countries, with an estimated
indicator of acute primary infection. Detection of virus global coverage of 46%.114 Pregnant women might be
needs to be interpreted in the light of serological results.81 screened for rubella antibody and offered post-partum
vaccination. High coverage of immunisation has led
Serological testing in pregnant women some high-income countries to drop rubella screening.
For rubella, T gondii, and cytomegalovirus, commercial Prenatal screening for toxoplasmosis is routinely
enzyme immunoassays are routinely available for undertaken in Austria, France, and Slovenia and neonatal
antibody detection. For cases of rubella and toxoplasmosis, screening is done in Denmark, Ireland, and some parts
serological diagnosis of acute primary infection relies on of the USA and Brazil.109 In France, women who develop
detection of acute phase IgM antibodies, which for most high titres of IgM antibodies or evidence of
individuals do not reach adequate levels until 1 week after seroconversion indicative of primary infection during
acute infection. For rubella, T gondii, and cytomegalovirus, pregnancy are offered fetal screening and treatment with
paired IgG samples taken at least 10–14 days apart should spiramycin or pyrimethamine. Severe sequelae from
also be obtained to confirm seroconversion. A 4-times congenital toxoplasmosis are now rarely seen after the
baseline rise in antibody titre is indicative of recent, approach of systematic prenatal screening and treatment
although not necessarily primary, infection.108 T gondii was implemented in France.37 Screening is being
IgM antibodies are commonly detected by ELISA in acute considered for cytomegalovirus in some high-income
infections, but might persist for several months.109 High countries and for Zika virus in countries with high rates
of transmission; however, screening is not recommended Normal head size Severe microcephaly
for either virus at present. Most prominent forehead area
Above ears above eyebrows
Clinical presentation at birth
Although infection can cause both primary and secondary
microcephaly, the main focus of this Review is the effect
of congenital infections on neurogenesis or antenatal
neural progenitor death usually associated with primary
microcephaly (ie, present at birth). Evaluation of an
infant with suspected microcephaly at birth seeks to
meet three goals: to confirm the diagnosis of Most prominent
occipital area
microcephaly, to identify the cause and attempt
syndromic diagnosis, and to aid prognosis and guide
initial treatment where appropriate.
Measurement of the occipitofrontal head circumference
(figure 3) is used as a screening examination to identify
neonates who are likely to have an underlying neurological
condition. A full antenatal history with particular focus on Figure 3: Measurement of occipitofrontal circumference in the neonate
Measurements of occipitofrontal head circumference can be variable and user dependent. A non-stretchable tape
acquired environmental insults, maternal serology, should be used to aid robust measurements and should be placed above the ears, covering the broadest part of the
antenatal fetal growth measurements where available, and forehead, and the most prominent area of the occiput as shown. The largest measured circumference of
family history of microcephaly and neurological three repeat measures should be used and recorded to the nearest millimetre. In neonates, the most robust
measurements are achieved at more than 24 h of age, when post-partum skull modelling has subsided.
conditions are essential to identify possible causes.
Systemic examination, including ophthalmology and
audiology, will help to identify associated abnormalities in
Panel: Clinical features suggestive of congenital infection
other organ systems. Cranial ultrasound can be used to
in a neonate with microcephaly115,116
screen for anatomical abnormalities where available.
Features suggestive of congenital infections in an infant • Severe microcephaly (<–3 Z scores)
with microcephaly are maternal history of infection • Intrauterine growth restriction
during pregnancy, indicative antenatal maternal serology • Hydrops fetalis
results, clinical features in the neonate (panel), and • Seizures
calcifications on brain imaging. In patients with these • Cataract and other visual abnormalities
features, more specific investigation is required, including • Hearing loss
serological testing to confirm specific infectious causes, • Congenital heart disease
other laboratory investigations, and further neuroimaging. • Hepatosplenomegaly
Common clinical features for each infection are shown • Jaundice
in the appendix and a summary of diagnosis and • Characteristic rashes See Online for appendix
treatment recommendations are given in table 2. Much
of this information is based on historical cohorts and
case studies and is therefore potentially prone to bias. of cutaneous, ophthalmological, and neurological abnor
Individual patients might present with different signs malities (including microcephaly). Vesicular lesions
and symptoms. might be present and often develop late. Perinatal
infection presents in three main ways: disseminated
Cytomegalovirus disease affecting multiple sites, CNS disease, or infection
Most neonates with congenital cytomegalovirus are limited to the skin, eyes, or mouth.30,31
asymptomatic, but common manifestations in
symptomatic neonates include intrauterine growth Rubella virus
restriction, sensorineural hearing loss, petechiae, and Fetal abnormalities resulting from in-utero transmission
jaundice. Neurological sequelae are observed in 60–90% of rubella virus range in severity according to gestational
of those with clinical symptoms at birth,123 although age at the time of infection. Infection in the first trimester
biases from early cohort studies might overestimate this is associated with more severe abnormalities.126
prevalence.87,124,125 Up to 15% of infants who are Symptomatic infection in the infant is referred to as
asymptomatic at birth might go on to develop symptoms congenital rubella syndrome, with a classic triad of
later in childhood.78,123,125 cataracts, sensorineural deafness, and cardiac defects (eg,
patent ductus arteriosus and ventricular septal defect).127
HSV Estimates of the frequency of microcephaly in congenital
Infection can occur in utero, intrapartum, or postnatally. rubella syndrome vary but have been reported to be as
In-utero infection is typically associated with a triad high as a third of cases overall.128
Diagnosis Treatment
Cytomegalovirus Cytomegalovirus viral culture or PCR testing for DNA from urine or saliva obtained Early treatment of confirmed symptomatic congenital cytomegalovirus with intravenous
within the first 3 weeks of life; retrospective diagnosis can be achieved from dried ganciclovir or oral valganciclovir is recommended based on the results of two main
blood samples taken for newborn screening; testing should be done as early as trials;117–119 results from randomised trials and observational studies have shown
possible improved hearing and neurodevelopmental outcomes, although questions remain
regarding optimal treatment strategies, including when to treat and duration of therapy
Herpes simplex PCR testing for viral DNA on surface swabs (conjunctivae and mucosal surfaces), Intravenous high-dose aciclovir is indicated for confirmed neonatal herpes simplex virus
virus 1 and 2 cutaneous lesions, CSF, whole blood, and tracheal secretions where available infections120
Rubella virus Isolation of rubella virus (or viral RNA) from the neonate, isolation of rubella IgM or Management is mainly supportive and involves monitoring for late emerging
persistent rubella IgG; the virus is most commonly isolated from nasopharyngeal symptoms (eg hearing loss and endocrine problems)
samples, but can be from blood, urine, and cerebrospinal fluid cultures121
Toxoplasma Diagnosis is difficult if specific IgM and IgA antibodies are not detected in the Congenital toxoplasmosis is treated with pyrimethamine and sulphadiazine or
gondii serum or plasma at birth; CSF samples to detect IgM and IgA antibodies might sulphadoxine with folinic acid to minimise pyrimethamine-associated haematological
confirm the diagnosis in infants with intracerebral lesions; maternal IgG is toxicity; up to 85% of children with subclinical congenital infection, if left untreated,
detectable in the fetus for several months, generally disappearing completely will later develop signs and symptoms of disease, such as chorioretinitis or
within a year; because specific IgG produced by congenitally infected newborns developmental delays122
might be detected about 12 weeks after birth, the presence of high IgG titres
beyond this time is suggestive of congenital infection109
Zika virus Testing for IgM antibody with capture ELISA using recombinant antigens in CSF or Clinical management of complications, including dysphagia, irritability, and epilepsy;
blood at birth indicate congenital infection; plaque reduction neutralisation tests supportive care for neurocognitive delays, hearing and visual loss, and appropriate
are required to confirm monotypic antibody responses, although dengue and developmental follow-up
yellow fever do not cause congenital infections; reverse-transcriptase PCR detects
acute infections, positivity is rare in neonates; tests can be done on serum or
plasma from cord blood or the infant’s peripheral blood; IgM detection in CSF of
neonates is highly specific
CSF=cerebrospinal fluid.
17 Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, 45 Mlakar J, Korva M, Tul N, et al. Zika virus associated with
Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine microcephaly. N Engl J Med 2016; 374: 951–58.
infection causes fetal brain abnormality and microcephaly: tip of 46 Feldman B, Yinon Y, Tepperberg Oikawa M, Yoeli R, Schiff E,
the iceberg? Ultrasound Obstet Gynecol 2016; 47: 6–7. Lipitz S. Pregestational, periconceptional, and gestational primary
18 Dolk H. The predictive value of microcephaly during the first year maternal cytomegalovirus infection: prenatal diagnosis in
of life for mental retardation at seven years. Dev Med Child Neurol 508 pregnancies. Am J Obstet Gynecol 2011; 4: e1–6.
1991; 33: 974–83. 47 Lipitz S, Yinon Y, Malinger G, et al. Risk of
19 Heinonen K, Räikkönen K, Pesonen AK, et al. Prenatal and postnatal cytomegalovirus-associated sequelae in relation to time of infection
growth and cognitive abilities at 56 months of age: a longitudinal and findings on prenatal imaging. Ultrasound Obstet Gynecol 2013;
study of infants born at term. Pediatrics 2008; 121: e1325–33. 41: 508–14.
20 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child 48 McAuley JB. Congenital toxoplasmosis. J Pediatric Infect Dis Soc
2013; 98: 707–13. 2014; 3 (suppl 1): S30–S35.
21 Krauss MJ, Morrissey AE, Winn HN, Amon E, Leet TL. Microcephaly: 49 Marquez L, Levy ML, Munoz FM, Palazzi DL. A report of three cases
an epidemiologic analysis. Am J Obstet Gynecol 2003; 188: 1484–89. and review of intrauterine herpes simplex virus infection.
22 O’Rahilly R, Müller F. Developmental stages in human embryos. Pediatr Infect Dis J 2011; 30: 153–57.
Washington: Carnegie Institution of Washington, 1987. 50 Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus
23 Chenn A, Walsh CA. Regulation of cerebral cortical size by control infections. J Pediatr 1987; 110: 97–101.
of cell cycle exit in neural precursors. Science 2002; 297: 365–69. 51 Barefoot KH, Little GA, Ornvold KT. Fetal demise due to herpes
24 Sahara S, O’Leary DD. Fgf10 regulates transition period of cortical simplex virus: an illustrated case report. J Perinatol 2002; 22: 86–88.
stem cell differentiation to radial glia controlling generation of 52 Odeberg J, Wolmer N, Falci S, Westgren M, Seiger A,
neurons and basal progenitors. Neuron 2009; 63: 48–62. Söderberg-Nauclér C. Human cytomegalovirus inhibits neuronal
25 Buchman JJ, Tseng HC, Zhou Y, Frank CL, Xie Z, Tsai LH. differentiation and induces apoptosis in human neural precursor
Cdk5rap2 interacts with pericentrin to maintain the neural progenitor cells. J Virol 2006; 80: 8929–39.
pool in the developing neocortex. Neuron 2010; 66: 386–402. 53 Johansson AB, Rassart A, Blum D, Van Beers D, Liesnard C.
26 Marthiens V, Rujano MA, Pennetier C, Tessier S, Paul-Gilloteaux P, Lower-limb hypoplasia due to intrauterine infection with herpes
Basto R. Centrosome amplification causes microcephaly. simplex virus type 2: possible confusion with intrauterine
Nat Cell Biol 2013; 15: 731–40. varicella-zoster syndrome. Clin Infect Dis 2004; 38: 57–62.
27 Chen JF, Zhang Y, Wilde J, Hansen KC, Lai F, Niswander L. 54 Lazar M, Perelygina L, Martines R, et al. Immunolocalization and
Microcephaly disease gene Wdr62 regulates mitotic progression of distribution of rubella antigen in fatal congenital rubella syndrome.
embryonic neural stem cells and brain size. Nat Commun 2014; EBioMedicine 2016; 3: 86–92.
5: 3885. 55 Dang J, Tiwari SK, Lichinchi G, et al. Zika virus depletes neural
28 Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids progenitors in human cerebral organoids through activation of the
model human brain development and microcephaly. Nature 2013; innate immune teceptor TLR3. Cell Stem Cell 2016; 19: 258–65.
501: 373–79. 56 Qian X, Nguyen HN, Song MM, et al. Brain-region-specific
29 Leruez-Ville M, Ville Y. Optimum treatment of congenital organoids using mini-bioreactors for modeling ZIKV exposure.
cytomegalovirus infection. Expert Rev Anti Infect Ther 2016; 14: 479–88. Cell 2016; 165: 1238–54.
30 Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus 57 Lafaille FG, Pessach IM, Zhang SY, et al. Impaired intrinsic
infections. Pediatr Clin North Am 2013; 60: 351–65. immunity to HSV-1 in human iPSC-derived TLR3-deficient
31 Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev CNS cells. Nature 2012; 491: 769–73.
2004; 17: 1–13. 58 Garcez PP, Loiola EC, Madeiro da Costa R, et al. Zika virus impairs
32 Kimberlin DW, Baley J. Guidance on management of asymptomatic growth in human neurospheres and brain organoids. Science 2016;
neonates born to women with active genital herpes lesions. 352: 816–18.
Pediatrics 2013; 131: e635–46. 59 Luo MH, Hannemann H, Kulkarni AS, Schwartz PH, O’Dowd JM,
33 Lee J, Bowden DS. Rubella virus replication and links to Fortunato EA. Human cytomegalovirus infection causes premature
teratogenicity. Clin Microbiol Rev 2000; 13: 571–87. and abnormal differentiation of human neural progenitor cells.
J Virol 2010; 84: 3528–41.
34 Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G. Viral
infections during pregnancy. Am J Reprod Immunol 2015; 73: 199–213. 60 Li XJ, Liu XJ, Yang B, et al. Human cytomegalovirus infection
dysregulates the localization and stability of NICD1 and Jag1 in
35 Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;
neural progenitor cells. J Virol 2015; 89: 6792–804.
363: 1965–76.
61 D’Aiuto L, Di Maio R, Heath B, et al. Human induced pluripotent
36 SYROCOT (Systematic Review on Congenital Toxoplasmosis) study
stem cell-derived models to investigate human cytomegalovirus
group, Thiebaut R, Leproust S, Chêne G, Gilbert R. Effectiveness of
infection in neural cells. PLoS One 2012; 7: e49700.
prenatal treatment for congenital toxoplasmosis: a meta-analysis of
individual patients’ data. Lancet 2007; 369: 115–22. 62 Rolland M, Li X, Sellier Y, et al. PPARγ is activated during
congenital cytomegalovirus infection and inhibits neuronogenesis
37 McLeod R, Kieffer F, Sautter M, Hosten T, Pelloux H. Why prevent,
from human neural stem cells. PLoS Pathog 2016; 12: e1005547.
diagnose and treat congenital toxoplasmosis?
Mem Inst Oswaldo Cruz 2009; 104: 320–44. 63 Braun E, Zimmerman T, Hur TB, et al. Neurotropism of herpes
simplex virus type 1 in brain organ cultures. J Gen Virol 2006;
38 Wikan N, Smith DR. Zika virus: history of a newly emerging
87: 2827–37.
arbovirus. Lancet Infect Dis 2016; 16: e119–26.
64 Hu S, Rotschafer JH, Lokensgard JR, Cheeran MC-J.
39 Waddell LA, Greig JD. Scoping review of the Zika virus literature.
Activated CD8+ T lymphocytes inhibit neural stem/progenitor cell
PLoS One 2016; 11: e0156376.
proliferation: role of interferon-gamma. PLoS One 2014; 9: e105219.
40 Bharucha T, Breuer J. Review: a neglected flavivirus: an update on
65 Nguyen TV, Pham VH, Abe K. Pathogenesis of congenital rubella
Zika virus in 2016 and the future direction of research.
virus infection in human fetuses: viral infection in the ciliary body
Neuropathol Appl Neurobiol 2016; 42: 317–25.
could play an important role in cataractogenesis. EBioMedicine 2014;
41 Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. 2: 59–63.
N Engl J Med 2016; 374: 1552–63.
66 Rorke LB, Fabiyi A, Elizan TS, Sever JL. Experimental cerebrovascular
42 Cooper LZ, Ziring PR, Ockerse AB, Fedun BA, Kiely B, Krugman S. lesions in congenital and neonatal rubella-virus infections of ferrets.
Rubella. Clinical manifestations and management. Am J Dis Child Lancet 1968; 2: 153–54.
1969; 118: 18–29.
67 Tondury G, Smith DW. Fetal rubella pathology. J Pediatr 1966;
43 Webster WS. Teratogen update: congenital rubella. Teratology 1998; 68: 867–79.
58: 13–23.
68 Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus
44 Driggers RW, Ho CY, Korhonen EM, et al. Zika virus infection with strain causes birth defects in experimental models. Nature 2016;
prolonged maternal viremia and fetal brain abnormalities. 534: 267–71.
N Engl J Med 2016; 374: 2142–51.
69 Tang H, Hammack C, Ogden SC, et al. Zika virus infects human 91 Looker KJ, Magaret AS, Turner KM, Vickerman P, Gottlieb SL,
cortical neural progenitors and attenuates their growth. Newman LM. Global estimates of prevalent and incident herpes
Cell Stem Cell 2016; 18: 587–90. simplex virus type 2 infections in 2012. PLoS One 2015;
70 Hamel R, Liégeois F, Wichit S, et al. Zika virus: epidemiology, 10: e114989.
clinical features and host-virus interactions. Microbes Infect 92 Vynnycky E, Adams EJ, Cutts FT, et al. Using seroprevalence and
2016; 18: 441–49. immunisation coverage data to estimate the global burden of
71 Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, congenital rubella syndrome, 1996–2010: a systematic review.
Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as PloS One 2016; 11: e0149160.
a candidate Zika virus entry receptor in neural stem cells. 93 WHO. Rubella. March, 2016. http://www.who.int/mediacentre/
Cell Stem Cell 2016; 5: 591–96. factsheets/fs367/en/ (accessed June 18, 2016).
72 Onorati M, Li Z, Liu F, et al. Zika virus disrupts phospho-TBK1 94 Pandolfi E, Gesualdo F, Rizzo C, et al. Global seroprevalence of
localization and mitosis in human neuroepithelial stem cells and rubella among pregnant and childbearing age women:
radial glia. Cell Rep 2016; 16: 2576–92. a meta-analysis. Eur J Public Health 2017; 27: 530–37.
73 Wells MF, Salick MR, Wiskow O, et al. Genetic ablation of AXL 95 Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: from
does not protect human neural progenitor cells and cerebral animals to humans. Int J Parasitol 2000; 30: 1217–58.
organoids from Zika virus infection. Cell Stem Cell 2016; 96 Jones JL, Kruszon-Moran D, Wilson M, McQuillan G, Navin T,
19: 703–08. McAuley JB. Toxoplasma gondii infection in the United States:
74 Pillai S, Nguyen J, Johnson J, Haura E, Coppola D, Chellappan S. seroprevalence and risk factors. Am J Epidemiol 2001; 154: 357–65.
Tank binding kinase 1 is a centrosome-associated kinase 97 Torgerson PR, Mastroiacovo P. The global burden of congenital
necessary for microtubule dynamics and mitosis. Nat Commun toxoplasmosis: a systematic review. Bull World Health Organ 2013;
2015; 6: 10072. 91: 501–08.
75 Li C, Xu D, Ye Q, et al. Zika virus disrupts neural progenitor 98 Wang ZD, Wang SC, Liu HH, et al. Prevalence and burden of
development and leads to microcephaly in mice. Cell Stem Cell 2016; Toxoplasma gondii infection in HIV-infected people: a systematic
19: 120–26. review and meta-analysis. Lancet HIV; 4: e177–88.
76 Wu KY, Zuo GL, Li XF, et al. Vertical transmission of Zika virus 99 Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on
targeting the radial glial cells affects cortex development of Yap Island, Federated States of Micronesia. N Engl J Med 2009;
offspring mice. Cell Res 2016; 26: 645–54. 360: 2536–43.
77 Adams Waldorf KM, Stencel-Baerenwald JE, Kapur RP, et al. 100 Aubry M, Teissier A, Huart M, et al. Zika virus seroprevalence,
Fetal brain lesions after subcutaneous inoculation of Zika virus in a French Polynesia, 2014–2015. Emerging Infect Dis 2017; 23: 669–72.
pregnant nonhuman primate. Nat Med 2016; 22: 1256–59. 101 WHO. Zika situation report. March 10, 2017. http://www.who.int/
78 Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. emergencies/zika-virus/situation-report/10-march-2017/en/
The “silent” global burden of congenital cytomegalovirus. (accessed March 31, 2017).
Clin Microbiol Rev 2013; 26: 86–102. 102 Coelho FC, Durovni B, Saraceni V, et al. Sexual transmission causes
79 Sheevani, Jindal N, Aggarwal A. A pilot seroepidemiological study a marked increase in the incidence of Zika in women in Rio de
of cytomegalovirus infection in women of child bearing age. Janeiro, Brazil. Int J Infect Dis 2016; 51: 128–32.
Indian J Med Microbiol 2005; 23: 34–36. 103 Health Protection Agency. Guidance on viral rash in pregnancy.
80 Schoenfisch AL, Dollard SC, Amin M, et al. Cytomegalovirus (CMV) Investigation, diagnosis and management of viral rash illness, or
shedding is highly correlated with markers of immunosuppression exposure to viral rash illness, in pregnancy. London: HPA, 2011.
in CMV-seropositive women. J Med Microbiol 2011; 60: 768–74. 104 Pass RF, Boppana S, Jeffries DJ, Hudson CN. Viral infection in
81 Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus obstetrics and gynaecology. New York: Arnold, 1999.
seroprevalence and demographic characteristics associated with 105 Best JM. Rubella. Semin Fetal Neonatal Med 2007; 12: 182–92.
infection. Rev Med Virol 2010; 20: 202–13.
106 Mendelson E, Aboudy Y, Smetana Z, Tepperberg M, Grossman Z.
82 Alanen A, Kahala K, Vahlberg T, Koskela P, Vainionpää R. Laboratory assessment and diagnosis of congenital viral infections:
Seroprevalence, incidence of prenatal infections and reliability of rubella, cytomegalovirus (CMV), varicella-zoster virus (VZV),
maternal history of varicella zoster virus, cytomegalovirus, herpes herpes simplex virus (HSV), parvovirus B19 and human
simplex virus and parvovirus B19 infection in South-Western immunodeficiency virus (HIV). Reprod Toxicol 2006; 21: 350–82.
Finland. BJOG 2005; 112: 50–56.
107 Lazzarotto T, Guerra B, Lanari M, Gabrielli L, Landini MP.
83 Seo S, Cho Y, Park J. Serologic screening of pregnant Korean New advances in the diagnosis of congenital cytomegalovirus
women for primary human cytomegalovirus infection using IgG infection. J Clin Virol 2008; 41: 192–97.
avidity test. Korean J Lab Med 2009; 29: 557–62.
108 Centers for Disease Control and Prevention. DPDx—laboratory
84 Kenneson A, Cannon MJ. Review and meta-analysis of the identification of parasitic diseases of public health concern.
epidemiology of congenital cytomegalovirus (CMV) infection. Toxoplasmosis. 2015. http://www.cdc.gov/dpdx/toxoplasmosis/dx.
Rev Med Virol 2007; 17: 253–76. html (accessed Oct 26, 2017).
85 Ornoy A, Diav-Citrin O. Fetal effects of primary and secondary 109 Petersen E. Toxoplasmosis. Semin Fetal Neonatal Med 2007;
cytomegalovirus infection in pregnancy. Reprod Toxicol 2006; 12: 214–23.
21: 399–409.
110 Dard C, Fricker-Hidalgo H, Brenier-Pinchart MP, Pelloux H.
86 Picone O, Vauloup-Fellous C, Cordier AG, et al. A series of Relevance of and new developments in serology for toxoplasmosis.
238 cytomegalovirus primary infections during pregnancy: Trends Parasitol 2016; 32: 492–506.
description and outcome. Prenat Diagn 2013; 33: 751–58.
111 Rorman E, Zamir CS, Rilkis I, Ben-David H. Congenital
87 Britt W. Controversies in the natural history of congenital human toxoplasmosis—prenatal aspects of Toxoplasma gondii infection.
cytomegalovirus infection: the paradox of infection and disease in Reprod Toxicol 2006; 21: 458–72.
offspring of women with immunity prior to pregnancy.
112 Alanen A, Hukkanen V. Herpes simplex virus DNA in amniotic
Med Microbiol Immunol 2015; 204: 263–71.
fluid without neonatal infection. Clin Infect Dis 2000; 30: 363–67.
88 Society for Maternal-Fetal Medicine, Hughes BL,
113 Calvet G, Aguiar RS, Melo AS, et al. Detection and sequencing of
Gyamfi-Bannerman C. Diagnosis and antenatal management of
Zika virus from amniotic fluid of fetuses with microcephaly in
congenital cytomegalovirus infection. Am J Obstet Gynecol 2016;
Brazil: a case study. Lancet Infect Dis 2016; 16: 653–60.
214: B5–11.
114 World Health Organization. Immunization coverage. Fact sheet.
89 Khamduang W, Jourdain G, Sirirungsi W, et al. The interrelated
March, 2017. http://www.who.int/mediacentre/factsheets/fs378/en/
transmission of HIV-1 and cytomegalovirus during gestation and
(accessed March 31, 2017).
delivery in the offspring of HIV-infected mothers.
J Acquir Immune Defic Syndr 2011; 58: 188–92. 115 Klein JO, Remington JS. Current concepts of infections of the fetus
and newborn infant. In: Remington JS, Klein JO, eds. Infectious
90 Looker KJ, Garnett GP, Schmid GP. An estimate of the global
disease of the fetus and newborn infant. 4th edn. Philadelphia:
prevalence and incidence of herpes simplex virus type 2 infection.
WB Saunders Co, 1995: 1–16.
Bull World Health Organ 2008; 86: 805–12.
116 Johnson KE. Overview of TORCH infections. 2015. 134 Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern
https://www.uptodate.com/contents/overview-of-torch-infections of anomalies in congenital Zika syndrome for pediatric clinicians.
(accessed May 17, 2016). JAMA Pediatr 2017; 171: 288–95.
117 Kimberlin DW, Jester PM, Sánchez PJ, et al. Valganciclovir for 135 Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus
symptomatic congenital cytomegalovirus disease. N Engl J Med infection: beyond neonatal microcephaly. JAMA Neurol 2016;
2015; 372: 933–43. 73: 1407–16.
118 Kimberlin DW, Lin CY, Sánchez PJ, et al. Effect of ganciclovir 136 Ventura CV, Maia M, Dias N, Ventura LO, Belfort R Jr. Zika:
therapy on hearing in symptomatic congenital cytomegalovirus neurological and ocular findings in infant without microcephaly.
disease involving the central nervous system: a randomized, Lancet 2016; 387: 2502.
controlled trial. J Pediatr 2003; 143: 16–25. 137 Reynolds MR, Jones AM, Petersen EE, et al. Vital signs: update on
119 Shah T, Luck S, Sharland M, Kadambari S, Heath P, Lyall H. Zika virus-associated birth defects and evaluation of all U.S. infants
Fifteen-minute consultation: diagnosis and management of with congenital Zika virus exposure—U.S. Zika pregnancy registry,
congenital CMV. Arch Dis Child Educ Pract Ed 2016; 101: 232–235. 2016. MMWR Morb Mortal Wkly Rep 2017; 66: 366–73.
120 Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of 138 Noyola DE, Demmler GJ, Nelson CT, et al. Early predictors of
high-dose intravenous acyclovir in the management of neonatal neurodevelopmental outcome in symptomatic congenital
herpes simplex virus infections. Pediatrics 2001; 108: 230–38. cytomegalovirus infection. J Pediatr 2001; 138: 325–31.
121 Plotkin SA, Reef SE, Cooper LZ, Alford CA. Rubella. In: 139 Abdel Razek AA, Kandell AY, Elsorogy LG, Elmongy A, Basett AA.
Remington JS, Klein JO, Wilson CB, Baker CJ, eds. Infectious Disorders of cortical formation: MR imaging features.
diseases of the fetus and newborn infant. 7th edn. Philadelphia, AJNR Am J Neuroradiol 2009; 30: 4–11.
PA: Elsevier Saunders, 2011: 861. 140 WHO. Psychosocial support for pregnant women and for families
122 Daffos F, Forestier F, Capella-Pavlovsky M, et al. with microcephaly and other neurological complications in the
Prenatal management of 746 pregnancies at risk for congenital context of Zika virus. Interim guidance for health-care providers.
toxoplasmosis. N Engl J Med 1988; 318: 271–75. Geneva: World Health Organization, 2016.
123 Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of 141 Centers for Disease Control. Facts about microcephaly. 2016.
congenital cytomegalovirus infection: disease mechanisms and http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html
prospects for intervention. Clin Microbiol Rev 2009; 22: 99–126. (accessed July 15, 2016).
124 Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence 142 Holt RL, Mikati MA. Care for child development: basic science
of neurological and sensory sequelae and mortality associated with rationale and effects of interventions. Pediatr Neurol 2011;
congenital cytomegalovirus infection. Rev Med Virol 2007; 44: 239–53.
17: 355–63. 143 Britto PR, Lye SJ, Proulx K, et al. Nurturing care: promoting early
125 Dreher AM, Arora N, Fowler KB, et al. Spectrum of disease and childhood development. Lancet 2016; 389: 91–102.
outcome in children with symptomatic congenital cytomegalovirus 144 The United Nations Children’s Fund. Violence against disabled
infection. J Pediatr 2014; 164: 855–59. children. UN Secretary Generals report on violence against
126 Miller E, Cradock-Watson JE, Pollock TM. Consequences of children. Thematic group on violence against disabled children.
confirmed maternal rubella at successive stages of pregnancy. Findings and recommendations. New York, NY: UNICEF, 2005.
Lancet 1982; 2: 781–84. 145 WHO, World Bank. World report on disability. Geneva: World
127 Givens KT, Lee DA, Jones T, Ilstrup DM. Congenital rubella Health Organization, 2011.
syndrome: ophthalmic manifestations and associated systemic 146 The United Nations Children’s Fund. The state of the world’s children
disorders. Br J Ophthalmol 1993; 77: 358–63. 2013. Children with Disabilities. New York, NY: UNICEF, 2013.
128 Reef SE, Plotkin S, Cordero JF, et al. Preparing for elimination of 147 Groce N. Disability, public health and social injustice. In: Levy B,
congenital Rubella syndrome (CRS): summary of a workshop on Sidel V, eds. Social injustice and public health. 2nd edn. Oxford:
CRS elimination in the United States. Clin Infect Dis 2000; Oxford University Press, 2014.
31: 85–95. 148 Yamin A. Health, human rights and the Zika virus. 2016.
129 Sabin AH. Toxoplasmosis. A recently recognized disease of https://fxb.harvard.edu/4941-2/ (accessed July 27, 2016).
human beings. Adv Pediatr 1942; 1: 1–53. 149 Palmer M. Disability and poverty: a conceptual review.
130 Cortina-Borja M, Tan HK, Wallon M, et al. Prenatal treatment for J Disabil Policy Stud 2011; 21: 210–18.
serious neurological sequelae of congenital toxoplasmosis: 150 Mitra S, Posarac A, Vick B. Disability and poverty in developing
an observational prospective cohort study. PLoS Med 2010; countries: a multidimensional study. World Development 2013;
7: e1000351. 41: 1–18.
131 Capobiango JD, Breganó RM, Navarro IT, et al. Congenital 151 UN. UN Convention on the Rights of Persons with Disabilities.
toxoplasmosis in a reference center of Parana, Southern Brazil. New York, NY: United Nations, 2006.
Braz J Infect Dis 2014; 18: 364–71.
132 Cauchemez S, Besnard M, Bompard P, et al. Association between
Zika virus and microcephaly in French Polynesia, 2013–15:
a retrospective study. Lancet 2016; 387: 2125–32.
133 Brasil P, Pereira JP Jr, Moreira ME, et al. Zika virus infection in
pregnant women in Rio de Janeiro. N Engl J Med 2016;
375: 2321–334.