An International Journal of Obstetrics and Gynaecology

Asymptomatic pregnant women returning to the United States from countries experiencing a Zika virus outbreak should be tested for Zika virus
FOR: Importance of identification in ALL pregnant women
JEANNE S SHEFFIELD, DIRECTOR OF MATERNAL-FETAL MEDICINE, JOHNS HOPKINS MEDICINE, BALTIMORE, MD, USA

AGAINST: Not so fast
GEORGE R. SAADE, PROFESSOR, OBSTETRICS AND GYNECOLOGY CHIEF OF
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These articles are part of a collection of articles on the Zika virus, introduced by an Editorial by SS Witkin. To view this Editorial visit http://dx.doi.org/I0.IIII/I47I-0528.I4076.

The Zika virus is a mosquito-borne flavivirus closely related to yellow fever and dengue viruses. It was first identified in 1947 in rhesus monkeys and subsequently noted to cause mild disease in humans throughout Africa and Asia. It was not until May 2015 that local transmission of the virus in the Americas was reported in Brazil. This virus has now spread throughout South and Central America and the Caribbean following the global distribution of the Aedes aegypti mosquito, with 41 countries and territories reporting active local transmission. Although the continental USA has not identified a case of local transmission, there are now > 350 confirmed travel- related Zika cases, a number of these being pregnant women.
The Brazilian outbreak of Zika virus was associated with a significant rise in microcephaly cases, first recognised in September 2015 (Schuler-Faccini et al. MMWR 2016;65:59-62). A number of other fetal abnormalities, including fetal growth restriction, intracranial calcifications, abnormal brainstem and cerebellum development, agyria with brain atrophy and absence of the corpus callosum and thalami, have now been documented. The virus has been identified in the brain of affected fetuses and infants.
It is unknown whether infants infected late in
pdated guidance issued in response to the recent reports of an association between maternal Zika infection and fetal microcephaly included a statement that serological testing for Zika virus can [emphasis added] be offered to asymptomatic pregnant women who travelled to an area with ongoing Zika virus transmission (SMFM Publications Committee Am J Obstet Gynecol 2016;pii:S0002-9378[16] 00343-4. doi: I0.I0I6/j.ajog.20I6.02.043; Oduyebo et al. MMWR 2016;65:122-7).
Testing in asymptomatic women focuses on Zika virus serum immunoglobulin M. Interpretation of serology results is complex and subject to false positives and false negatives, particularly when it is used as a screen for maternal to fetal transmission, the ultimate reason for testing. The value of a screening test depends on its predictive performance and on the a priori risk in the target population, in this case asymptomatic pregnant women who travelled to an affected area. There are no data on the sensitivity, specificity, false positives or false negatives in such cases. Moreover, the a priori risk of infection in an asymptomatic pregnant woman who travelled to an affected area, let alone the risk of having an affected fetus, is not known. This a priori risk is probably close to zero. As of 24 February 2016, no confirmed cases of maternal infection were identified among 162 asymptomatic pregnant women tested by the Centers for Disease Control and Prevention (CDC; 95%
pregnancy that have not had time to develop microcephaly and other abnormalities before delivery will have long-term sequelae.
It is estimated that 40 million people travel between the continental USA and Zika-affected areas each year. Although the vast majority of travellers are not infected and those that do become infected usually do not have symptoms, transmission from a pregnant woman to her fetus may have devastating consequences. The Centers for Disease Control and Prevention recommend that all pregnant women who travel to Zika-affected areas, regardless of symptoms, be screened for Zika virus upon return (Oduyebo et al. MMWR 2016;65:122- 7). Although a key priority is to reduce the risk of Zika acquisition in pregnancy through preventive measures, for those women who do travel, screening upon return will allow for identification of infected women. The interpretation of serological tests for Zika virus is complex, but a negative IgM obtained 2-12 weeks after travel should help to tailor management.
A positive serological test, regardless of symptomatology, will prompt the physician to perform serial ultrasounds to identify fetal intracranial abnormalities and
CI for maternal infection 0% to 2.2%) (Fleming-Dutra et al. MMWR 2016;65:182-7). All nine women with confirmed maternal infection, including four women with likely fetal infection, had a generalised rash, as well as other symptoms in eight of the women (Fleming-Dutra et al. MMWR 2016;65:182-7). In a more recent update released on April 15, 2016, the CDC reported that Zika infection was confirmed in 7 of 2425 pregnant women who were asymptomatic (maternal infection rate 0.3%; 95% CI 0.1% to 0.6%). Only 2 of the confirmed infections were in women who were short-term travellers. The remaining 5 were residing in affected areas at some time during their pregnancy (Dasgupta et al. MMWR 20I6;65:395 99). So regardless of the test likelihood ratios, the post-test probability in asymptomatic women is likely to be zero and most positive tests are likely to be false positives. This highlights the unintended consequences and the potential to do more harm with testing. These unintended consequences include risks ofamniocentesis, termination of a normal pregnancy and maternal anxiety.
The benefit of a screening test also depends on what is done next. As there is no treatment, the rationale for testing so far has been to assist in counselling women about fetal risks, whether to perform amniocentesis, and whether to continue serial ultrasound. Data on which to base counselling or decision-making for any of these downstream actions, other than the
microcephaly. The pregnant woman may also be offered an amniocentesis for Zika reverse transcription-polymerase chain reaction at > 15 weeks of gestation. The results of these evaluations will allow the family to make informed decisions regarding the pregnancy. It will help to prepare the family as to what to expect at delivery, and the physician as to what services will be required. An infant born to an infected mother will be followed longitudinally for any late-onset complications.
Although most cases of affected fetuses/neonates to date have been in symptomatic mothers, both symptomatic and asymptomatic pregnant women are presumed to be at risk. Appropriate identification of ALL infected pregnant women will allow for appropriate evaluation and management of their respective fetus/neonate. It will also help to better inform the global effort to understand this unique and devastating disease.
Disclosure of interests
None declared. Completed disclosure of interests form available to view online as supporting information. I risk of pregnancy loss from amniocentesis, are not readily available. We do not know the rates of fetal infection with either a positive or negative serological test in an asymptomatic woman, and the rates of fetal abnormalities with either a positive or negative amniocentesis.
Some of the same organisations that recommend testing in this situation have rightly recommended against cell-free DNA testing in low-risk women (SMFM Publications Committee Am J Obstet Gynecol 2015;212:711-16). The rationale was that the performance of cell-free DNA in low-risk women is not known. We actually know a lot more about its performance than we know about Zika virus serological testing, and the outcome being screened for with cell-free DNA is as devastating as microcephaly. So why the difference? Could it be a reaction to the panic and widespread media frenzy? Until additional data become available, I suggest that we follow the original guidance from the CDC, which did not recommend serological testing in asymptomatic women (Petersen et al. MMWR 2016;65:30-3).
Disclosure of interests
None declared. Completed disclosure of interests form available to view online as supporting information. I

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© 2016 Royal College of Obstetricians and Gynaecologists