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CONFLICT OF INTEREST
Dr. Mitchell receives research support from
pharmaceutical companies, including support
from Seqirus to study the safety of Afluria vac-
cine in pregnancy and from GSK to develop a
protocol for studying the safety of an asthma
drug in pregnancy. Dr. Mitchell is a member of
Biogen’s Tecfidera Pregnancy Registry Advisory
Committee.
VC 2016 ASCPT
1. Thorpe, P.G. et al. and the National Birth
Defects Prevention Study. Medications in the
first trimester of pregnancy: most common
exposures and critical gaps in understanding
fetal risk. Pharmacoepidemiol. Drug Saf. 22,
1013–1018 (2013).
2. Van Bennekom, C.M., Parker, S.E., Anderka,
M., Louik, C. & Mitchell, A.A. Ondansetron
for the treatment of nausea and vomiting of
pregnancy and the risk of birth defects
[Abstract]. Pharmacoepidemiol. Drug Saf.
24(suppl. 1), 401–402 (2015).
3. Mitchell, A.A. Systematic identification of
drugs that cause birth defects—a new
opportunity. N. Engl. J. Med. 349, 2556–
2559 (2003).
4. Mitchell, A.A. Studies of drug–induced birth
defects. In Pharmacoepidemiology 5th ed
(eds. Strom, B.L., Kimmel, S.E. & Hennessy,
S.) 487–504 (West Sussex, UK: Wiley-
Blackwell, 2012).
5. Mitchell, A.A. et al. and the National Birth
Defects Prevention Study. Medication use
during pregnancy, with particular focus on
prescription drugs: 1976-2008. Am. J.
Obstet. Gynecol. 205, 51.e1–8 (2011).
6. Werler, M.M. et al. and the National Birth
Defects Prevention Study. Use of over-the-
counter medications during pregnancy. Am.
J. Obstet. Gynecol. 193, 771–777 (2005).
7. FDA Public Meeting: Study Approaches and
Methods to Evaluate the Safety of Drugs and
Biological Products During Pregnancy in the
Post-Approval Setting, May 28–29, 2014.
<http://www.regulations.gov/#!docket
Detail;D5FDA-2014-N-0157>. Accessed 24
February 2016.
8. Schatz, M., Chambers, C.D., Jones, K.L.,
Louik, C. & Mitchell, A.A. The safety of
influenza immunizations and treatment
during pregnancy: the Vaccines and
Medications in Pregnancy Surveillance
System. Am. J. Obstet. Gynecol. 204(6 suppl.
1), S64–S68 (2011).
9. U.S. Food and Drug Administration: Pregnancy
and Lactation Labeling (Drugs) Final Rule.
<http://www.fda.gov/Drugs/
DevelopmentApprovalProcess/
DevelopmentResources/Labeling/ucm093307.
htm>. Accessed 14 February 2016.
Zika Virus: A New Human
Teratogen? Implications for
Women of Reproductive Age
L Schuler-Faccini1,2, MTV Sanseverino1,2, FSL Vianna1,2,
AA da Silva1,3, M Larrandaburu1,2, C Marcolongo-Pereira4 and
AM Abeche1,5
In 2015 an unprecedented increase of reports of newborns with
microcephaly in Brazil made news headlines around the world. A
possible etiological association with prenatal maternal infection
by Zika virus (ZIKV) was suggested based on temporal and
geographic distribution of ZIKV infection and the subsequent
increase in the reports of microcephaly cases. Here we discuss
ZIKV as a new human teratogen, with comments on potential
treatment options.
IS ZIKA VIRUS A NEW HUMAN
TERATOGEN?
To answer this question properly we will
examine evidence according to Shepard’s
amalgamation of criteria for proof of
human teratogenicity.1
Transplacental passage
Cases of Brazilian fetuses were diagnosed
with microcephaly during pregnancy in
which ZIKV was detected through reverse-
transcription polymerase chain reaction
(RT-PCR) in the amniotic fluid.2 A Slove-
nian woman who had rash and fever at the
end of her first trimester of pregnancy when
she was living in Brazil requested termina-
tion of the pregnancy after an ultrasound at
29 weeks revealed fetal microcephaly and
brain calcifications. The complete genome
of the ZIKV was recovered from the fetal
brain.3
Epidemiological link
Oliveira et al.4 analyzed the birth prevalence
of microcephaly in Brazil through the Live
Birth Certificate notification, and observed
a sharp increase in the number of microce-
phaly cases during 2015–2016. They identi-
fied temporal and geospatial correlation
between the occurrence of maternal febrile
rash illness and the emergence of microce-
phaly in the offspring. One prospective Bra-
zilian study reported the outcomes of 88
pregnant women (72 of them were tested
positive for ZIKV) who developed rash in
the previous 5 days. Of the 58 women who
had Doppler fetal ultrasonography, fetal
abnormalities were detected in 12/42 (29%)
ZIKV-positive women, but in none of 16
ZIKV-negative women. Cauchemez et al.5
retrospectively analyzed serological and sur-
veillance data from the 2013–2014 ZIKV
outbreak in French Polynesia. They esti-
mated an absolute risk of microcephaly
1SIAT, Brazilian Teratogen Information Service, Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Brazil; 2Post-Graduate Program in Genetics and
Molecular Biology, Federal University of Rio Grande do Sul, Brazil; 3UNIVATES University, Brazil; 4Veterinary Sciences Faculty, UniRitter Laureate International
Universities, Brazil; 5Obstetrics and Gynecology Department, Federal University of Rio Grande do Sul, Brazil. Correspondence: L Schuler-Faccini (lavinia.
faccini@ufrgs.br)
doi:10.1002/cpt.386
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associated with ZIKV infection ranging
from 34 to 191/10,000 women infected
during the first trimester of pregnancy.
They could not evaluate risks associated
with infection in the second or third
trimester.
Distinct symptomatology
A consistent clinical pattern of the sug-
gested Zika embryopathy is emerging.6 The
observations from published cases show
microcephaly (usually head circumference
below 3 SD of the mean) with marked
head/face disproportionality, scalp and/or
occipital redundant skin folds, and promi-
nent occiput. Clubfoot and arthrogryposis
are frequently seen and might represent a
consequence of the cortical damage. On
neurological examination, the infants pres-
ent irritability, hyperreflexia, hypertonia or
spasticity, tremors, and seizures. Macular
atrophy in the retina was observed and des-
cribed. Brain abnormalities observed by ne-
uroimaging and postmortem exams include
markedly small brains, ventriculomegaly,
multifocal brain calcifications, abnormal
gyration (agyria, lissencephaly, polymicro-
gyria), and severe abnormalities of midline
structures and the cerebellum, suggesting
early damage of the developing brain.
Although some of these characteristics are
common to congenital infections as brain
calcifications, in general the clinical effect is
much more severe than cytomegalovirus,
rubella, or toxoplasmosis.
Rare exposure and rare defect
This criterion is not valid for ZIKV infec-
tion, because of a wide exposure and a
prevalent outcome (microcephaly).
Teratogenicity in experimental animals
Zika is an arbovirus member of the Flavi-
viridea family. Many arboviruses are known
to act as teratogens with a preeminent neu-
rotropism in domestic and wild animals
both experimentally and as in naturally
occurring infections. In ruminants, pigs,
and sheep some viruses in this group pro-
duce a phenotype quite similar to Zika
infection in humans, including hydranence-
phaly, porencephaly, microencephaly, cere-
bellar hypoplasia, chorioretinopathy, and
arthrogryposis.7
Biological plausibility
Finally, it has been shown that a Zika
strain (MR766) is able to infect human
neural progenitor cells (hNPCs), and dys-
regulates cell-cycle progression, increases
cell death, and alters global gene expression.
In their experiment, hNPCs were the
direct target of ZIKV.8
As described above, evidence of ZIKV as
a human teratogen is accumulating. How-
ever, the exact probability of the fetal dam-
ages after maternal ZIKV infection is not
yetknown, including pregnancy stage-
specific risks. Most of the cases described in
the literature are of severe brain damage
caused after infection in the first half of
pregnancy. As described above, the study
from Brazil followed women with con-
firmed ZIKV infection at any time during
pregnancy and detected 29% of abnormal-
ities among 42 women who underwent pre-
natal ultrasonographic studies.4 Besides the
brain abnormalities, the authors observed
increased fetal loss, placental insufficiency,
and fetal growth restriction. It is possible,
therefore, that brain destruction might be
only part of a spectrum of neurological
damage, and there is still a gap of knowl-
edge of the third trimester outcomes after
infection.
The clinical progression of affected new-
borns is related to the severity of the brain
damage. Newborns examined frequently
show neurological abnormalities: hyperto-
nia or spasticity, tremors, irritability, hyper-
reflexia, and seizures. However, at present
we cannot predict the long-term cognitive/
neurological development of those with
milder brain abnormalities or even without
clinical signs at birth, including normal
head circumference.
WHAT ARE THE IMPLICATIONS FOR
WOMEN OF REPRODUCTIVE AGE?
POSSIBILITIES OF TREATMENT AND
PREVENTION
The amount of evidence now strongly sug-
gests that ZIKV is a new human teratogen.
Effective vaccine or treatment is not avail-
able yet and many questions are still unan-
swered, with important implications for the
counseling of women of reproductive age.
Moreover, advice is different for women
residing in regions with active ZIKV trans-
mission from those who do not.
Modes of transmission and contagious
periods
The main mode of transmission of ZIKV
is through the bite of infected Aedes mos-
quitoes. However, there are some case
reports of sexual transmission from the
male to his sexual partners, and ZIKV was
detected in semen up to 62 days after infec-
tion, prompting advice to men with ZIKV
disease to avoid attempting conception for
at least 6 months after symptoms.9
Although transplacental transmission has
been confirmed, there is no evidence that
ZIKV can cause congenital infection in
pregnancies conceived after the resolution
of maternal viremia. Women are advised to
wait 8 weeks to attempt conception after
the beginning of the symptoms if she had
the symptomatic infection. Both women
and men with possible exposure to ZIKV
(travel or residence in an area of active
ZIKV), but asymptomatic should also wait
at least 8 weeks after exposure to attempt
conception.9 It is not known, however, if
ZIKV infection provides a long-lasting
immunity, like rubella, for example.
Diagnosis
The gold standard is the gene-detection
test by RT-PCR on serum to detect virus,
viral nucleic acid. However, the majority of
exposures to ZIKV may cause an asymp-
tomatic infection, so the large majority of
infected pregnant women may remain
undiagnosed. Serological tests can be diffi-
cult to interpret because ZIKV is closely
linked to dengue, and the serologic samples
may crossreact.
Vaccines
Efficient vaccines are already available for a
number of flavivirus, such as yellow fever
(live attenuated virus). Recently, the tetrava-
lent chimeric live attenuated dengue vaccine
was approved for use in several dengue-
endemic countries. Therefore, although not
presently available, similar approaches are
being explored to advance vaccine for ZIKV.
Potential treatment of viremia
Current therapeutic options for flavivirus
infections are essentially based on support-
ive care. No specific antiviral therapy is
approved for ZIKV (nor for any flavivirus).
Supportive care includes rest, antipyretics,
analgesics, and antihistamines for
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cutaneous symptoms if necessary. Nonster-
oidal antiinflammatory drugs (NSAIDs)
and aspirin should be delayed until dengue
can be ruled out to reduce the possibility of
hemorrhagic complications. Due to its sim-
ilarity to dengue, some antiviral therapies
can be explored. A few agents like chloro-
quine, balapiravir, and celgosivir were
already assessed by clinical trials in dengue-
infected humans. Unfortunately, there was
no evidence of effective reduction in
plasma viremia.10 Moreover, we do not
know much about the biology of the Zika
virus and if it is similar to dengue. There-
fore, animal models are essential for vaccine
and therapeutic development. Recently,
Tang et al.8 were able to establish an exper-
imental system based on ZIKV infection of
hNPCs that can provide a platform to
screen therapeutic compounds. Finally,
since pregnant women will be the major
target for ZIKV therapy, the potential tera-
togenicity or toxicity of the drug itself
should be carefully considered in the selec-
tion of a potential antiviral therapy.
CONCLUSION
While effective vaccines or antiviral treat-
ment is not available, prevention of ZIKV
infection is crucial. Effective control of the
vector is mandatory. Women of reproduc-
tive age should be fully informed about the
risks and protective measures to avoid mos-
quito bites if they live or travel to regions
where active transmission is ongoing. Pre-
conception counseling, family planning, and
contraceptive methods should be immedi-
ately provided and of easy access for every
woman, independent of socioeconomic sta-
tus. Guidance for healthcare providers car-
ing for women of reproductive age with
possible ZIKV exposure is published and
periodically updated by the Centers for Dis-
ease Control and Prevention.9
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
VC 2016 ASCPT
1. Shepard, T.H. “Proof” of human
teratogenicity. Teratology 50, 97–98 (1994).
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pregnant women in Rio de Janeiro—
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3. Mlakar, J. et al. Zika virus associated with
microcephaly. N. Engl. J. Med. 374,
951–958 (2016).
4. Oliveira, W.K. et al. Increase in reported
prevalence of microcephaly in infants born
to women living in areas with confirmed
zika virus transmission during the first
trimester of pregnancy—Brazil, 2015.
MMWR Morb. Mortal. Wkly. Rep. 65,
242–247 (2016).
5. Cauchemez, S. et al. Association between
Zika virus and microcephaly in French
Polynesia, 2013-15: a retrospective
study. Lancet (2016); e-pub ahead of
print (doi: 10.1016/S0140-
6736(16)00651-6).
6. Schuler-Faccini, L. et al. Possible
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and microcephaly—Brazil, 2015. MMWR
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7. Agerholm, J.S. et al. Virus-induced
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8. Tang, H. et al. Zika virus infects human
cortical neural progenitors and attenuates
their growth. Cell StemCell<http://dx.doi.
org/10.1016/j.stem.2016.02.016> (2016).
9. Petersen, E.E. et al. Interim guidance for
health care providers caring for women of
reproductive age with possible zika virus
exposure—United States, 2016. MMWR
Morb. Mortal. Wkly. Rep. (2016); e-pub
ahead of print.
10. Simmons, C.P. et al. Recent advances in
dengue pathogenesis and clinical
management. Vaccine 33, 7061–7068
(2015).
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