Interim RCOG/RCM/PHE/HPS clinical guidelines

Zika Virus Infection and Pregnancy

Information for Healthcare Professionals

Zika virus (ZIKV) is an emerging viral infection with increasing transmission in South
and Central America over the past few months.1 ZIKV is transmitted by the Aedes
mosquito, which is present throughout Africa, South and South East Asia, South and
Central America, the Caribbean and the Pacific. The majority of people infected with
ZIKV have minimal symptoms; in those who do have symptoms, ZIKV tends to cause
a mild febrile illness which is short lived and rarely causes significant pathology in the
infected individual.2 However, it is possible that when contracted in pregnancy it may
lead to fetal microcephaly, although it is not yet clear whether this association is
causal or whether additional factors are involved. In November 2015, the Brazilian
Ministry of Health declared a public health emergency following reports of a 20-fold
increase in the number of babies born with microcephaly, suggesting a potential link
with the ongoing outbreak of ZIKV infection in the region.

Epidemiology

ZIKV was first discovered in a Rhesus monkey in Uganda in 1947 and in humans a
few years later, yet few outbreaks have been documented.1 The first ZIKV outbreak
reported outside of Africa and Asia occurred in Micronesia in 2007. This was
followed by an outbreak of the same strain in French Polynesia in 2013; since then
there have been major outbreaks in other parts of the Pacific.1

Brazil reported its first case of local transmission of ZIKV in May 2015. Since then
the virus has spread rapidly; as of 27 January 2016, ZIKV transmission is occurring in
23 countries and territories in South/Central America and the Caribbean, as well as in
countries outside this region.3 The list of countries with active ZIKV transmission will
be updated weekly on the Zika page of the Public Health England (PHE) website
(https://www.gov.uk/guidance/zika-virus) and a map is available on the ECDC
website (http://ecdc.europa.eu/en/healthtopics/zika_virus_infection/zikaoutbreak/Pages/Zika-information-travellers.aspx). As of 29 January 2016, countries
currently experiencing active transmission are: Barbados, Bolivia, Brazil, Cape
1

Verde, Colombia, Dominican Republic, Ecuador, El Salvador, French Guiana,

Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Martinique, Mexico, Nicaragua,
Panama, Paraguay, Puerto Rico, Saint Martin, Samoa, Suriname, Thailand,
Venezuela, US Virgin Islands.
This rapid spread over the past few months is mainly due to two factors:4
1. The population in this part of the world had not previously been exposed to ZIKV
and so lacked immunity.
2. Aedes mosquitoes, the main vector for ZIKV transmission, are present in all of
these regions/countries in the Americas, apart from Canada and continental Chile.

It is likely that this rapid spread of ZIKV will continue until it reaches all countries of
the region where the Aedes mosquito is found.4

ZIKV has not occurred naturally in the UK because we do not have the vectors - the
climate is currently not suitable for the Aedes mosquito to survive. However,
imported cases have occurred in the UK in travellers that have returned from South
and Central America (as well as one from the Cooks Islands in 2014)
(https://www.gov.uk/guidance/zika-virus).3

Transmission

ZIKV is transmitted by the bite of an infected female Aedes mosquito. Various

species of Aedes mosquito may have the potential to transmit ZIKV, but the most
commonly associated with ZIKV is Aedes aegypti.5 After an infected mosquito bites a
human, the first symptoms of ZIKV can develop in 3 to 12 days but it can be shorter
or longer in some people.
In general, this is the mode of transmission of the virus, human-mosquito-human, and
direct human to human transmission does not occur. There is circumstantial evidence
to suggest that sexual transmission of the virus in human semen can occur

6,7 but

more evidence is required to confirm whether or not this is possible. ZIKV can be
transmitted by blood transfusion but standard precautions for ensuring safe blood
donations and transfusions should prevent this.

Cases of maternal fetal transmission have been confirmed. There is currently no

evidence that ZIKV can be transmitted to babies through breast milk and the advice
to mothers to breastfeed remains unchanged.4

Symptoms

The incubation period of ZIKV (the time from infection by mosquito bite to the first
symptoms) appears to be 3 to 12 days for most people. The majority of infected
individuals have minimal symptoms.8,9 Typical symptoms may include: a low grade
fever, maculopapular rash which may be itchy, non-purulent conjunctivitis/red eyes,
arthralgia (with possible swelling, mainly in the smaller joints of the hands and feet),
myalgia, headache, and eye pain. Even in those with symptoms, ZIKV infection is
usually a mild, short-lived illness, lasting only 2-7 days. There is no evidence that
pregnant women are more vulnerable to acquiring ZIKV infection or that this infection
causes a more serious illness in pregnant women.

The symptoms of ZIKV infection are similar to those of dengue fever (caused by a
related flavivirus) and chikungunya (an alphavirus). These two infections are also
transmitted by the Aedes mosquito and so are found in the same geographical areas.
Differential diagnosis therefore requires laboratory testing (see Diagnosis below).10

Serious complications from ZIKV are uncommon. However, an increase in cases of

fetal microcephaly,1 Guillain-Barre syndrome and other neurological and autoimmune
syndromes has been reported in areas where ZIKV outbreaks have occurred. 11
Although these associations cannot yet be said to be causal, emerging evidence
suggests that they may be. In November 2015, four perinatal deaths from ZIKV
infection associated with microcephaly were reported in Brazil.12

During another large ZIKV outbreak in French Polynesia in 2013, the national health
authority there reported an increase in neurological and autoimmune conditions that
were potentially complications of ZIKV infection. Three countries (Brazil, El Salvador
and Venezuela) have reported cases of Guillain-Barre syndrome in individuals with
symptoms suggestive of ZIKV infection but this potential association continues to be
investigated.12

ZIKV in the Americas and Microcephaly

3

In October 2015, the Brazilian Ministry of Health reported an apparent rapid increase
in the number of babies born with microcephaly and the following month declared this
a public health emergency. As of 23 January 2016, 4,180 cases of suspected
microcephaly, including 68 deaths, had been reported across 24 states in Brazil 13
(representing a rate approaching 300:100,000 live births). This was in marked
contrast to the 150-200 cases per year that were reported between 2010 and 2014
(5.7:100,000 live births in 2010).

It is not yet certain whether maternal ZIKV infection is responsible for the increase in
cases of fetal microcephaly in Brazil. However, supporting evidence is mounting.
There is a temporal association: the increase in cases of microcephaly started within
nine months of the outbreak of ZIKV in northern Brazil.1,14 It has been demonstrated
that ZIKV can cross the placental barrier and the virus has been detected in blood
and tissues of at least seven affected fetuses/infants; the mothers of six of these
cases presented with symptoms consistent with ZIKV infection during pregnancy.15-17
The gestation at which the infection is acquired may be important; one study of 35
cases of microcephaly in Brazil found that 26 (74%) of the women reported having
had a rash, 21 in the first trimester, 5 in the second trimester and none in the third
trimester.18 Based on this information and on experience from other congenital
infections such as CMV, rubella and toxoplasmosis, it is likely that ZIKV infection in
early pregnancy poses the greatest risk.

Coinciding with outbreaks of ZIKV in French Polynesia in 2014-2015, 17 cases of

fetal and neonatal central nervous system malformations were reported.12 Four of
these women were tested and had detectable IgG antibodies to flavivirus; further
tests are ongoing. However, as yet no increase in cases of microcephaly has been
reported from other countries affected by outbreaks of ZIKV and investigations
continue to try to establish whether the association between ZIKV and microcephaly
is causal.

Diagnosis

The diagnosis of ZIKV infection should be considered among individuals returning

from South or Central America, the Caribbean, or the Pacific region who developed a
fever and/or other symptoms suggestive of ZIKV while abroad or within two weeks of
4

returning to the UK.10 Healthcare providers should ask all pregnant women about
recent and planned travel. The mainstay of testing for ZIKV in maternal serum is
reverse transcription polymerase chain reaction (RT-PCR) for symptomatic patients
with onset of symptoms within the previous week. Antibody testing is less reliable
due to potential cross-reaction with antibodies against other similar viruses (e.g.
dengue or yellow fever, which are often co-located), making it difficult to differentiate
ZIKV infection using antibody testing alone.10
ZIKV RT-PCR can also be performed on amniotic fluid13,16 although it is currently not
known how sensitive or specific this test is for congenital infection, or the likelihood of
an infected fetus being affected, i.e. subsequently developing a fetal abnormality.

In the UK, samples for testing for ZIKV should be sent to Public Health England
(PHE) Rare and Imported Pathogens Laboratory (RIPL)
(https://www.gov.uk/government/collections/rare-and-imported-pathogens-laboratoryripl). RIPL is a specialist centre for advice and diagnosis for a wide range of unusual
viral and bacterial infections including ZIKV.

Treatment

There is no specific antiviral treatment for ZIKV. However, as mentioned above,

ZIKV infection is usually mild and short-lived, and requires no specific treatment. If
symptoms are troublesome, a pregnant woman should be advised to get plenty of
rest, drink adequate fluids and manage pain and fever with regular paracetamol and
other cooling measures. In the unlikely event that symptoms become more severe,
she should seek medical advice.

Prevention

There is currently no vaccine or drug available to prevent ZIKV infection. The Aedes
mosquito, the main vector for ZIKV, is active predominantly during daylight hours;
bites are most common during mid-morning and late afternoon to dusk, when the
mosquito is most active. This is in contrast to the Anopheles mosquito which
transmits malaria and which is more active by night. Travellers to countries with
ongoing outbreaks of ZIKV should take all possible measures to minimise the
chances of mosquito bites. This includes wearing light-coloured, loose-fitting clothes
5

that cover as much exposed skin as possible, for example long trousers and long
sleeves. Because the Aedes mosquito is active during daylight hours, it is important
that travellers to these areas cover up during the daytime as much as possible.
Clothing can be treated with an insecticide (e.g. permethrin) which kills insects,
including mosquitoes, on contact.19

N, N-diethyl meta toluamide (DEET) based repellents are the most effective insect
repellents widely available, and have been in use for over 50 years. Preparations
with concentrations of DEET up to 50% are commonly available and are safe in
pregnant and breastfeeding women (and in infants and children over the age of 2
months).19,20 Care should be taken to ensure that insect repellents are not ingested,
and that they do not come in contact with the eyes or mouth.

Insect repellents should be re-applied regularly, particularly after swimming and in hot
humid conditions when they may be removed by perspiration. When both sunscreen
and insect repellents are required, the insect repellent should be applied over the
sunscreen. DEET based repellents can reduce the sun protection factor (SPF) of
sunscreen so pregnant women should consider wearing a higher factor sun cream
(SPF 30-50) when also using DEET based repellents.19

The following are not recommended as insect repellents: Citronella Oil based
repellents (these have a very short duration of action), vitamin B12 complex, vitamin
B1, tea tree oil.19

Travellers staying in accommodation without screening should sleep under a

mosquito net, particularly in malaria risk areas. Those sleeping during the day in an
area with ZIKV should sleep under a mosquito net (if sleeping in accommodation
without screening). Ideally, nets should be impregnated with permethrin or another
contact insecticide. Retreatment after six months of use is necessary.19

Advice for Pregnant Women

In the UK, the National Travel Health Network and Centre (NaTHNaC) now advises
that pregnant women should consider avoiding travel to countries where ZIKV
outbreaks are ongoing, in order to reduce the risk to their babies
(http://travelhealthpro.org.uk/zika-virus-update-and-advice-for-travellers-including6

pregnant-women/).21 An ongoing outbreak is defined as active ZIKV transmission,

i.e. locally acquired cases reported in the last 6 months. Health Protection Scotland
give similar advice to carefully consider travel plans in view of the ZIKV risk, via
TRAVAX (www.travax.nhs.uk) and FitforTravel (www.fitfortravel.nhs.uk). Pregnant
women who must travel (or choose to travel) to a country with an ongoing ZIKV
outbreak should take all necessary precautions to minimise the chances of a
mosquito bite, as described above. Pregnant women recently returned to the UK
from countries with an ongoing outbreak of ZIKV should inform their obstetrician,
midwife or GP that they may have been exposed to the Zika virus so that they can be
monitored and/or tested.

In the United States, the Centers for Disease Control and Prevention (CDC) now
recommends that all pregnant women should consider postponing travel to areas
where ZIKV transmission is ongoing;22 a number of other countries have issued
similar advice. The WHO has stopped short of recommending that pregnant women
should postpone travel to these countries.4

Recommendations for pregnant women who have travelled to an area of ZIKV

transmission

Knowledge about ZIKV and pregnancy is limited and still evolving. Recommendations
are based on current information and are likely to be updated periodically to reflect
emerging evidence. The Figure describes the currently recommended assessment
algorithm.

Women reporting symptoms consistent with ZIKV disease

Healthcare providers should ask all pregnant women about recent travel. Pregnant
women with a history of travel to an area with active ZIKV transmission and who
present with symptoms consistent with ZIKV disease during or within two weeks of
travel, should be tested for ZIKV infection and other travel associated infections
(including malaria) by submitting appropriate samples to RIPL (Figure). Where ZIKV
is identified on laboratory testing, the woman should be referred to a fetal medicine
service for further assessment. If the test for ZIKV is negative, serial (4-weekly) fetal
ultrasound scans should be considered to monitor fetal growth and anatomy. Testing
for ZIKV is not recommended for women whose symptoms have resolved by the time
of presentation, but they too should be offered serial (4-weekly) fetal ultrasound
7

scans. Routine testing of asymptomatic women (those who remained asymptomatic

while travelling and for two weeks after their return from a ZIKV affected area) is not
recommended. However, serial fetal ultrasound scans as above should be
considered (as ZIKV infection is associated with minimal symptoms in the majority).

Any woman in whom a small fetal head (Head Circumference more than 2 Standard
Deviations below the mean for gestational age, i.e. below the 2.5th centile) or brain
abnormality (such as intracranial calcifications) is diagnosed on ultrasound, and who
has previously visited a ZIKV affected area during pregnancy, should also be referred
to a maternal fetal medicine service for further assessment. Though the majority of
babies with a Head Circumference more than 2 SD below the mean will be normal
and will not have microcephaly, referral to a specialist fetal medicine service is
recommended. Microcephaly is usually diagnosed when baby's Head Circumference
is even smaller than this, and usually together with structural abnormalities of the
brain that can be diagnosed with specialist imaging'. Women with a diagnosis of fetal
microcephaly or intracranial calcifications but who have not travelled to a ZIKV
affected area during pregnancy do not need to be tested.

If fetal microcephaly or brain abnormality, such as intracranial calcification, is

diagnosed, consideration should be given to performing an amniocentesis to test for
the virus using RT-PCR. However, this decision should be taken only after careful
counselling. Amniocentesis is associated with a small risk of miscarriage or preterm
birth and should not be performed before 15 weeks of gestation. As discussed above,
even if positive, it is not known how sensitive or specific this test is for congenital
infection, nor the likelihood of an infected fetus being affected. Nevertheless, if there
is fetal abnormality on ultrasound and ZIKV PCR on amniocentesis is positive, then it
is highly likely that the abnormality is ZIKV associated and that the outcome is likely
to be poor. When brain abnormalities are identified on ultrasound scan, consideration
should be given to performing fetal brain MRI which may detect abnormalities that
have not been detected on ultrasound. When a significant brain abnormality or
microcephaly is confirmed in the presence of ZIKV infection, the option of termination
of pregnancy should be discussed with the woman, regardless of gestation.

Women planning pregnancy

Women should be advised to avoid becoming pregnant while travelling in an area
with active ZIKV transmission. On returning to the UK, they should avoid becoming
8

pregnant for a further 28 days; this allows for a maximum two week incubation period
and possible two-week viraemia.

Women whose partner has been to an area with ZIKV transmission

As discussed above, the risk of sexual transmission of ZIKV is thought to be very low.
However, ZIKV has been identified in semen of men who have had ZIKV infection,
and it is not known how long this can persist. If a womans partner has travelled to a
country with active ZIKV transmission, effective contraception is advised to avoid
pregnancy (and the use of condoms could be considered to prevent against infection
acquisition):
for 28 days after his return home if he had no ZIKV symptoms, either whilst
abroad or within 2 weeks of his leaving the affected country
for 6 months following recovery if he did experience ZIKV symptoms during that
period

Following Birth

Following a live birth where there has been laboratory confirmation of maternal or
fetal ZIKV infection, the following tests are recommended:
Histopathological examination of the placenta and umbilical cord
Testing of placental tissue and cord tissue for ZIKV RNA
Testing of umbilical cord blood for ZIKV and dengue virus.
These babies should be followed up into childhood for signs of any adverse effects of
the congenital ZIKV infection.

A proportion of other pregnant women who have travelled to areas with active ZIKV
transmission but have no confirmed diagnosis, will have had unidentified ZIKV
infection. There is debate as to whether these children should also be followed up
after birth; further advice on this question will be published at a later date.

In case of fetal loss in a woman with a history of travel during pregnancy to an area
with active ZIKV transmission and who had symptoms consistent with ZIKV infection
during or within two weeks of travel, or fetal microcephaly, discuss with RIPL, who
are likely to request samples of fetal tissue, including umbilical cord and placenta for
ZIKV RT-PCR. Immunohistochemical staining of the placenta should also be
performed.
9

The reason for this testing is to gain potentially valuable information about the
pathophysiology of ZIKV in pregnancy and to aid in further counselling of the woman.
Figure. Interim1 algorithm for assessing pregnant women with a history of travel
during pregnancy to areas with active ZIKV transmission.2

Notes
1. Interim guidance will be updated as more information becomes available.
Currently this algorithm applies to women at all stages of pregnancy although
based on information available from Brazil and experience from other
congenital infections, such as CMV, rubella and toxoplasmosis, infection in
early pregnancy is likely to pose the greatest risk.
2. Laboratory testing is performed by the PHE Rare and Imported Pathogens
Laboratory (RIPL). Given the overlap of symptoms and endemic areas with
other viral and bacterial infections, RIPL will routinely test symptomatic
pregnant women returning from ZIKV-affected areas for dengue, chikungunya
and other infections as well as ZIKV. ZIKV testing will be performed
exclusively using real-time PCR rather than any serology test.
10

3. Countries currently reporting ZIKV outbreaks:

http://www.cdc.gov/zika/geo/index.html
4. Clinical illness is consistent with ZIKV disease if two or more symptoms (acute
onset of fever, maculopapular rash, arthralgia, or conjunctivitis) are present.
However, testing can also be considered for pregnant women with acute
onset of symptoms within 2 weeks of travel to an area with ZIKV transmission
that are not explained by other common infectious causes (e.g. URTI, UTI).
5. The samples required are a clotted blood (or serum), an EDTA purple top
blood (or plasma) and a small volume of urine without preservative. The
samples must be submitted with a single RIPL request form,
https://www.gov.uk/government/publications/rare-and-imported-pathogenstesting-form-to-submit-sample . The form must clearly state the pregnancy
gestation and both the travel history (ie which countries visited and the dates
of the outward and return journeys) and the clinical details (ie the patients
symptoms and the date of illness onset). This is so that the appropriate
investigations can be performed and their results correctly interpreted.
6. If an alternative diagnosis is made, there is no need for further ZIKV-specific
follow-up.
7. For women without current symptoms, taking and storing a clotted serum
sample locally is recommended.
8. This evaluation and follow-up is likely to include repeat fetal ultrasound at fourweekly intervals, and consideration of fetal MRI. Abnormal fetal findings will
prompt appropriate investigation including, for example, submission of booking
and current serum samples for toxoplasma, rubella, parvovirus and CMV
serology. Amniocentesis may be considered for ZIKV PCR.
9. In this context small (fetal) head is defined as: Head Circumference more
than 2 Standard Deviations below the mean for gestational age, i.e. below the
2.5th centile.
10. Apart from microcephaly and intracranial calcifications, other brain
abnormalities that have been reported in association with ZIKV infection are
ventriculomegaly, cell migration abnormalities (e.g. lissencephaly, pachygyria),
arthrogryposis (congenital contractures) secondary to central or peripheral
nervous system involvement.

11

References

1. CDC. Zika Virus. http://www.cdc.gov/zika/geo/index.html

2. Pan American Health Organization. Question and Answers: Zika and Pregnancy.
http://www.paho.org/hq/index.php?option=com_content&view=article&id=11552&Ite
mid=41672&lang=en
3. Health protection guidance. Zika Virus. https://www.gov.uk/guidance/zika-virus
4. PAHO Statement on Zika Virus Transmission and Prevention.
http://www.paho.org/hq/index.php?option=com_content&view=article&id=11605&It
5. Hayes EB. Zika virus outside Africa. Emerg Infect Dis 2009;15:134750.
6. Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus.
Emerg Infect Dis 2015;2:359-61.
7. Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable non-vector-borne
transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011;17: 880882. doi:
10.3201/eid1705.101939
8. CDC. Zika virus. Atlanta, GA: US Department of Health and Human Services,
CDC; 2016. http://www.cdc.gov/zika/index.html.
9. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island,
Federated States of Micronesia. N Engl J Med 2009;360:253643.
10. Petersen EE, Staples JE, Meaney-Delman, D, et al. Interim Guidelines for
Pregnant Women During a Zika Virus Outbreak United States, 2016. MMWR Morb
Mortal Wkly Rep 2016;65:3033. DOI: http://dx.doi.org/10.15585/mmwr.mm6502e1
11. Oehler E, Watrin L, Larre P, et al. Zika virus infection complicated by GuillainBarre syndromecase report, French Polynesia, December 2013. Euro Surveill
2014;19:46.
12. Pan American Health Organization / World Health Organization. Epidemiological
Update: Neurological syndrome, congenital anomalies and Zika virus infection. 17
January, Washington, D.C.: PAHO/WHO; 201
http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270
&gid=32879&lang=en
13. http://portalsaude.saude.gov.br/images/pdf/2016/janeiro/28/COES-Microcefalias--Informe-Epidemiol--gico-10---SE-03-2016---26jan2016---20h34.pdf
14. European Centre for Disease Prevention and Control. Rapid risk assessment.
Zika virus epidemic in the Americas: potential association with microcephaly and
Guillain-Barr syndrome. Stockholm, Sweden: European Centre for Disease
Prevention and Control; 2015.
12

http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-associationwith-microcephaly-rapid-risk-assessment.pdf
15. CDC. CDC health advisory: recognizing, managing, and reporting Zika virus
infections in travelers returning from Central America, South America, the Caribbean
and Mexico. Atlanta, GA: US Department of Health and Human Services, CDC;
2016. http://emergency.cdc.gov/han/han00385.asp.
16. Besnard M, Lastere S, Teissier A, Cao-Lormeau V, Musso D. Evidence of
perinatal transmission of Zika virus, French Polynesia, December 2013 and February
2014. Euro Surveill 2014;19:136.
17. Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo
de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and
microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol 2016;47:67.
18. Centres for Disease Control and Prevention Morbidity and Mortality Weekly
Report. Possible Association Between Zika Virus Infection and Microcephaly - Brazil,
2015. Weekly / January 29, 2016 / 65(3);5962.
http://www.cdc.gov/mmwr/volumes/65/wr/mm6503e2.htm
19. Insect and tick bite avoidance. http://travelhealthpro.org.uk/insect-tick-biteavoidance/
20. CDC. Travelers health: avoid bug bites. Atlanta, GA: US Department of Health
and Human Services, CDC; 2013. http://wwwnc.cdc.gov/travel/page/avoid-bug-bites.
21. National Travel Health Network and Centre. Zika virus: update and advice for
pregnant women. http://travelhealthpro.org.uk/zika-virus-update-and-advice-forpregnant-women/
22. CDC. Travelers health. CDC issues interim travel guidance related to Zika virus
for 14 countries and territories in Central and South America and the Caribbean.
Atlanta, GA: US Department of Health and Human Services, CDC; 2016.
http://wwwnc.cdc.gov/travel/notices.

This document was last updated on 05/02/16

13