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Review

Infectious causes of microcephaly: epidemiology,


pathogenesis, diagnosis, and management
Delan Devakumar, Alasdair Bamford, Marcelo U Ferreira, Jonathan Broad, Richard E Rosch, Nora Groce, Judith Breuer, Marly A Cardoso,
Andrew J Copp, Paula Alexandre, Laura C Rodrigues, Ibrahim Abubakar

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

www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5 1


Review

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).

2 www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5


Review

Pathogenesis and embryology


The CNS becomes established from day 22 of embryonic Severe reduction in numbers of Microcephaly
neural progenitors and neurons (small brain)
development, when the neural tube is formed.22 The
embryonic brain is initially composed entirely of
proliferative neuronal progenitors, which reside within Neural progenitor death or
the ventricular zone that borders the neural tube lumen. 10-week-old cell cycle arrest
human brain
However, with subsequent development, neurons begin
to emerge and a new population of deeper subventricular
zone neural progenitors arises. Proliferation of the Presumptive
cortical plate
subventricular zone cells contributes to further expansion Neuron
of the brain’s neuronal population. Proliferative ven­ Subventricular
tricular zone and subventricular zone neuronal zone
progenitors persist until around mid-gestation, providing Ventricular
a target for pathogens via the cerebral blood supply, which zone Neural
progenitor
is now fully established. Experimental evidence shows
that regulation of neural progenitor numbers and Proliferation stimulus Differentiation stimulus

subtypes is essential for controlling brain size and


morphology (figure 2). For example, mouse studies reveal Increases numbers of neural Premature neuronal differentiation
that abnormal expansion of the ventricular zone or progenitors and neurons
subventricular zone neural progenitors increases brain
size and produces macrocephaly.23,24 By contrast, a
Macrocephaly (big brain) Microcephaly (small brain)
reduction in neural progenitor numbers due to cell death,
cell cycle arrest, or premature neuronal differentiation
Figure 2: Factors that might affect neuronal and neural progenitor
reduces brain size and produces microcephaly.25–28 populations and lead to microcephaly or macrocephaly
The pathogenesis of cytomegalovirus, HSV, rubella, and
Zika virus is described subsequently. Little information is
available on the mechanisms of congenital brain infection impair neuronal differentiation, and a PPARγ inhibitor
for T gondii, and additional research is needed. The restored normal differentiation. Moreover, nuclear PPARγ
congenital infections we describe in this Review (table 1) was detected in the brains of congenitally infected
are responsible for a range of developmental brain defects, fetuses.62 These findings support a role for PPARγ in
with more severe cases occurring after infection during mediation of congenital cytomegalovirus brain disease.
the first trimester of gestation, when the neural
progenitors are actively multiplying and producing HSV
neurons (figure 2).42–51 Analysis of material from aborted HSV can infect multiple brain cell types (in vivo [human
human fetuses confirms that brain cells are susceptible to brain after clinical infection],50,53 in vitro [induced
viral infection (Zika virus,45 cytomegalovirus,52 HSV,50,53 pluripotent stem cells and human embryonic stem cell
and rubella).54 Moreover, human cell culture systems show derived neural stem cells, and astrocytes in culture],57 and
that neural progenitors are targeted by these pathogens mouse [in-vitro brain slice culture]),63 but it is unclear how
(Zika virus brain organoids,55,56 HSV-induced pluripotent such infection leads to microcephaly. Infected organs,
stem cell-derived cell culture,57 Zika virus neurospheres,58 including the brain, show post-mortem tissue necrosis.51
and cytomegalovirus neural precursors).52 This research In-vitro and animal studies suggest that HSV might
suggests that perturbation of neural progenitor initially induce an immune response that stimulates
populations might be the main cause of infection-related neural stem cell proliferation. Subsequently, brain
microcephaly. infiltration by CD8 T cells limits proliferation through the
stimulation of interferon γ.64 Operation of a similar
Cytomegalovirus immune-mediated mechanism following congenital brain
Cytomegalovirus is capable of altering progenitor and infection leading to micro­cephaly is possible but remains
neuronal fates through the downregulation of multi­ to be verified.
potency markers, including Sox2 and Nestin.59,60 Neuronal
differentiation has been found to be inhibited or delayed Rubella virus
by cytomegalovirus52,61,62 or to occur prematurely after The mechanisms by which rubella virus induces
infection.59 A new molecular mechanism downstream of microcephaly remain largely unknown. Most human
cytomegalovirus brain infection has emerged: peroxisome embryonic tissues can be infected by rubella virus54,65 and
proliferator-activated receptor γ (PPARγ) was found to brain vessels have been found to degenerate following
increase following cytomegalovirus infection of human rubella infection.65–67 These observations suggest that a
neural stem cells and human fetal brain sections. neurodegenerative mechanism could be a potential
Activation of PPARγ function alone was sufficient to underlying cause of rubella-induced microcephaly in

www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5 3


Review

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

Table 1: Summary of microbiological, virological, and maternal clinical features of microcephaly

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

4 www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5


Review

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

www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5 5


Review

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

6 www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5


Review

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

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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.

Table 2: Diagnosis and treatment of infants with infectious causes of microcephaly

T gondii of congenital Zika syndrome includes birth defects


Approximately 24% of liveborn infants infected with associated with microcephaly (including hearing loss and
T gondii are symptomatic at birth.36 The classic signs ophthalmological defects) and how these factors are
originally described by Sabin129 (chorioretinitis, related to timing of infection; presence or absence of
microcephaly, or hydrocephalus, and widespread maternal symptoms; and the influence of other arboviral
intracranial calcifications) are relatively infrequent, but infections, which has yet to be fully delineated. Most of
highly suggestive of congenital toxo­ plasmosis. Severe what is known about congenital Zika syndrome comes
manifestations occur in infections early in gestation. from neonates with microcephaly, which appears to
Intracranial lesions, for example, are seen in up to 40% include syndrome-specific features such as partly
of congenital infections acquired before 5 weeks of collapsed skull, reduced cortical thickness, and extensive
pregnancy, but in less than 10% of those acquired beyond subcortical calcifications.134,135 However, the full spectrum
20 weeks.36 12·5% of liveborn infants with congenital will only become clear when cohort studies of infected
toxoplasmosis develop severe neurological sequelae;130 mothers provide in-depth reports of clinical presentation.
5% of liveborn infants with congenital toxoplasmosis Brain damage or ocular lesions can be found in the
have microcephaly.131 absence of microcephaly and other features are common
(appendix).16,136,137 It remains to be shown whether viral
Zika virus replication is ongoing at the time of birth in congenital
Zika virus infection in pregnancy and its possible link to a Zika virus infection, which will have important
range of birth defects is the subject of intense investigation implications for the potential efficacy of postnatally
worldwide. Convincing evidence exists that Zika virus administered antiviral therapy.
infection in pregnancy, especially in the first trimester, is
associated with an increased risk of microcephaly. The Markers for prognosis
risk associated with Zika virus infection was estimated to Microcephaly outcomes are varied, and more accurate
be 95 per 10 000 infected women in the first trimester in prognosis at the time of diagnosis is one of the main aims
French Polynesia.132 Congenital disease has predominantly of clinical evaluation of the neonate. Neuroimaging—for
been seen in Brazil, but could spread across Latin example cranial ultrasound, CT, and MRI—has proven a
America. Brasil and colleagues133 followed up 117 babies of useful predictive investigation and is warranted in
Zika virus-affected pregnant women in Rio de Janeiro neonates with severe microcephaly, or where a congenital
and found that four (3·4%) had microcephaly and 49 infection is suspected.138 Although different modalities
(42%) had abnormal clinical or radiological findings in have specific advantages (eg, good visibility of calcifications
the first month, mostly affecting the CNS. The spectrum on CT, and bedside availability of cranial ultrasound),

8 www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5


Review

many structural abnormalities caused by disruptions in


development can be identified across modalities. Typical Search strategy and selection criteria
abnormalities include intracranial calcifications, white We searched PubMed, Embase, and Google Scholar with no
matter abnormalities (eg, periventricular leukomalacia language or date restrictions (search end date
and delayed myelination, which are best seen on March 31, 2017), for the following terms: “Cytomegalovirus”
MRI), gyration defects (eg, polymicrogyria), and schiz­ or “CMV” or “Rubella” or “MMR” or “Zika” or “HSV” or
encephaly.14,139 “herpes” or “toxoplasma” or “toxoplasmosis” and
“seroprevalence” or “prevalence” or “incidence”; “congenital
Long-term consequences and resulting disability pathogenic infections” or “pathogenic infections” and “brain
in childhood disorders” or “microcephaly”; “pathogens” or “virus” or
Long-term follow-up is recommended for infants with “pathogen” or “viral” and “microcephaly”; “Cytomegalovirus”
microcephaly, even for those with congenital infections or “CMV” or “Rubella” or “MMR” or “Zika” or “HSV” or
who are apparently unaffected at birth, to manage “herpes” or “toxoplasma” or “toxoplasmosis” and “brain” or
evolving conditions and identify new manifestations “brain disorder” or “brain development” or “brain defects”;
early. In many cases, the cause of microcephaly will not “cytomegalovirus” or “rubella” or “toxoplasmosis” or “herpes
be known and generic plans can be adopted to manage simplex” or “varicella” or “chikungunya” or “West Nile virus”
impairments and limit disability. The timing of or “HIV” or “syphilis” and “microcephaly” not “Zika”. We also
interventions varies in importance. For example, hearing searched reference lists of identified studies.
screening needs to be done early to enable interventions
to optimise language development. Other interventions,
including psychosocial support and counselling,140 are management, support, or advocacy needs beyond pre-
required throughout childhood and into adult life. school years. Although attitudes vary from society to
When microcephaly occurs, early intervention is society, overwhelmingly, people with disabilities face
recommended to address associated impairments, calling increased risk of stigma, social isolation, abuse, and
upon a host of specialist medical and educational poverty across their lifespan.147
services.141 Regular follow-up is recommended for Zika Infections that cause microcephaly are likely to
virus associated microcephaly for anthropometry, disproportionately affect low-income and middle-income
developmental, and neurological assessments, and also countries, and within these countries the poorest
hearing and ophthalmological assessment when required populations, who are most likely to live in crowded areas
over the first 2 years, with less frequent follow-up recom­ with inadequate housing and insufficient water and
mended for infants without microcephaly.3 Evidence- sanitation systems. Compounding these issues, poor
based therapy strategies exist that might improve cognitive women are less likely than rich women to have access to
outcomes and reduce disability.142 Interventions in early family planning services, prenatal screening or, if
life, for example child stimulation,143 maximise the needed, safe termination of pregnancy.148
plasticity of the developing brain, attenuating the Although social protection schemes are beginning in
consequences of damage to the nervous system. But such many middle-income countries,149 the cost of raising and
recommendations ignore the realities of life in many supporting a disabled child continues to be borne almost
countries. Issues begin at birth, for example, in some entirely by the immediate family. Households with
locations children with visible disabilities are allowed to disabled members are, on average, poorer because of
die in the neonatal period, either through active infanticide increased costs and because family members, in
or through withdrawal of basic care such as feeding.144 particular women, must take time away from income-
The provision of both recommended early diagnosis generating activities to provide care.150
and appropriate interventions might be severely limited Improved services and support for affected individuals
in countries with very few specialists, where early and families across the lifespan should be anticipated,
intervention programmes or inclusive education efforts and health professionals should work with civil society
remain rare and largely urban based. Based on a small organisations, including disabled people’s organisations,
but growing literature on disability, individuals with to ensure these children and their families receive the
more severe disabilities are far less likely than their medical, educational, and social service support they
healthy peers to receive appropriate medical care, attend need and to which they are entitled.151
school, or be included in the social, economic, or
religious life of their communities.145 This inequity is Conclusions
compounded in poorer households, which often choose We have summarised the epidemiology, clinical
to invest limited resources in non-disabled children, presentation, and understanding of the pathogenesis of
whom they feel will be able to contribute to the major congenital infections associated with microcephaly.
household in future.146 Furthermore, recommendations Potential inconsistencies in the criteria used to diagnose
for individuals with microcephaly tend to concentrate on microcephaly have been highlighted, in addition to
early childhood, but anticipate little about their limitations of current diagnostic methods in confirming

www.thelancet.com/infection Published online August 22, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30398-5 9


Review

an infectious aetiology. If microcephaly, as strictly Contributors


defined by head circumference, is used as a screening DD and IA conceived this Review. AB, DD, JoB, MUF, PA, and RER
undertook the literature reviews. AB, AJC, DD, JoB, JuB, LCR, MAC,
tool, it will miss affected infants who do not manifest MUF, NG, PA, and RER wrote sections of the draft. All authors
with a small head size. Many infants are likely to have interpreted and critically revised the draft.
subtle deficits needing more sensitive neurological and Declaration of interests
developmental assessments. Microcephaly is also usually We declare no competing interests.
only one manifestation in a syndrome and other Acknowledgments
assessments are required to identify the full spectrum of We thank Fabien Lafaille (St Giles Laboratory of Human Genetics of
illness. Infectious Diseases, The Rockefeller University, New York, NY, USA)
who advised on herpes simplex virus and brain development; and the
Zika virus has brought the attention of the world to the
Joint Medical Research Council/Wellcome Trust (099175/Z/12/Z)
problem of microcephaly. The extent of the disease Human Developmental Biology Resource for providing the human brain
burden resulting from Zika virus is still being clarified section shown in figure 2. DD receives salary support from the UK
but it appears to be substantial and is one of a number of National Institute for Health Research (NIHR), and PA receives salary
support from the Royal Society, Dorothy Hodgkin Fellowship. IA is
infections associated with primary microcephaly. On
supported by the NIHR (SRF-2011-04-001; NF-SI-0616-10037).
an individual level, accurate diagnosis and thorough JuB receives funding from the NIHR UCL/UCLH Biomedical Research
investigation of confirmed microcephaly can guide Centre. LCR is partially funded by the European Union’s Horizon 2020
management and determine prognosis. On a population research and innovation programme under Zika-PLAN grant agreement
no 734584.
level, assessment of the overall burden and contribution
of different causes will guide future interventions and References
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