Zika Refresher

About the Webinar

This webinar explains how Zika virus is contracted, prevention methods, who should be assessed for Zika virus exposure, current testing recommendations, and what follow-up is recommended for the infants of women with possible Zika virus exposure during pregnancy.

This webinar was supported by Cooperative Agreement 6NU38OT000167-04-06 from the Centers for Disease Control and Prevention and the American Academy of Pediatrics. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the American Academy of Pediatrics.

For additional information from the Centers for Disease Control and Prevention (CDC), visit their webpage on Zika and Pregnancy. The CDC also has a variety of Zika resources, including fact sheets for patients and providers and testing algorithms.

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Video Transcript

Moderator: Hello and thank you for joining us today. My name is Don from Blue Sky. Today's webcast is entitled Zika Refresher: The Latest Recommendations on Counseling, Testing, and Management of Zika Virus in Pregnant Women. We'll focus on how Zika virus is contracted, prevention methods, who should be assessed for Zika virus exposure, current testing recommendations and what follow-up is recommended for the infants of women with possible Zika virus exposure during pregnancy.

This webinar is supported by the cooperative agreement from the Centers for Disease Control and Prevention and the American Academy of Pediatrics. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the American Academy of Pediatrics.

The faculty and planning committee wish to disclose the following information.

And now, please let me introduce our program faculty for today's webcast. Dr. Titi Oduyebo is a medical officer in the Division of Reproductive Health at the Centers for Disease Control and Prevention. She's a subject matter expert on emerging infections and reproductive health and has co-authored numerous articles including clinical guidelines for Zika virus prevention. We'd like you to please review the learning objectives now for this presentation. We'll give you a moment to look at those before we move on.

And now, ladies and gentlemen with no further ado, I'll turn things over to Dr. Titi Oduyebo. Dr. Oduyebo, the audience is all yours.

Titilope Oduyebo, MD: Good afternoon everyone and good morning to those who are behind the Eastern Standard Time. I'm very excited to be here today and honored to have been asked to speak with you about the CDC's guidance for health care providers caring for pregnant women and for non-pregnant women of reproductive age. Thank you all so much for taking time to attend this talk and thank you to the American College of Obstetrics and Gynecology for organizing this webinar.

First, I would like to briefly provide an overview of Zika virus which most likely is a review for most, if not all of you. Zika virus is a single-stranded RNA virus which is closely related to dengue, yellow fever, Japanese encephalitis and West Nile viruses. It is primarily transmitted by two Aedes species mosquitoes, Aedes aegypti and Aedes albopictus mosquitoes.

As you know, and will be discussed later, the Zika virus may also be transmitted through several other routes including intrauterine and perinatal transmission, sexual transmission, laboratory exposure and probable blood transfusion. However, prior to the most recent outbreak, these modes of transmission were not discovered. Although research is underway, there is currently no vaccine or specific antiviral treatment for Zika virus.

Particularly about the Zika … more information about Zika virus vaccine, there are now greater than 40 vaccines that have been developed by the US government agencies, commercial vaccine manufacturers and academic research labs. With at least six candidate vaccines being evaluated in clinical trials, there's one vaccine that has begun its phase 2b study to evaluate the safety and efficacy.

The cornerstone of clinical management is supportive care. Patients should be advised to treat the symptoms including recommending rest, drinking fluids, taking medicine such as acetaminophen to reduce fever and pain. Aspirin and other non-steroidal anti-inflammatory drugs or NSAIDs should be avoided until dengue has been ruled out as a cause of illness in order to reduce the risk of bleeding and it should also be avoided in children aged less than six months.

In terms of Zika virus infection during pregnancy, prior to the 2015 outbreak, the limited information that we had demonstrated that there were no evidence of increased susceptibility of Zika virus among pregnant women. Zika virus infection could occur in any trimester. However, the incidence of Zika virus infections in this group were not known and that the clinical course is similar among pregnant women and non-pregnant individuals.

So everyone kept asking if the clinical symptoms that typically mount, if present at all, why is there so much concern about Zika virus infection? This brings us to the lessons learned from the most recent Zika virus outbreak. Although Zika virus has existed for almost 70 years, the potentially devastating effects on pregnancy have only been recently observed.

To quote our former CDC director, Dr. Frieden, “never before in history has there been a situation where a bite from a mosquito could result in a devastating malformation.” Some of you may remember that the last time an infectious pathogen, which was rubella virus, caused an epidemic of congenital defects was more than 50 years ago. This was before an effective vaccine became available.

Early in this response, we all were faced with many questions, and in a short amount of time, we had to learn a lot about the association of Zika virus and the poor pregnancy outcomes. CDC in collaboration with state, tribal, local, and territorial health departments in the United States and the US territories established several surveillance systems of pregnant women, fetuses, and infants called the US Zika Pregnancy and Infant Registry and the US Zika Birth Defects Surveillance.

The data from the surveillance systems were used and continue to be used to inform the clinical guidance and to direct public health actions. We just wanted to say a big, special thank you to all of you on the phone. I'm sure many of you had contact and have reported patients to the registry, your health department, and then to the registry. So thank you. We couldn't do this surveillance system without your time and effort.

These two systems I just discussed are very complementary. The US Zika Pregnancy and Infant Registry prospectively follows pregnant women with any laboratory evidence of Zika and their infants, while the Zika-related Birth Defects Surveillance system monitors for brain abnormalities including microcephaly and other central nervous system defects to better understand Zika exposure during pregnancy and adverse outcomes. This is more done retrospectively.

Using the data from these surveillance systems as well from other published reports, CDC and other scientists have established that the Zika virus is a cause of serious brain abnormalities, microcephaly, and other birth defects. Also recognize the pattern of birth defects associated with Zika virus, congenital Zika virus infections, now called congenital Zika syndrome. It also provided clues towards the level of the risk from congenital Zika virus infection, which we'll go more into shortly, and also identify that Zika virus infection during all trimesters have been associated with birth defects.

The distinct pattern of birth defects among the fetuses and infants born to women infected during pregnancy, which is called congenital Zika syndrome, include severe microcephaly with partially collapsed skull; thin cerebral cortex with calcifications noted in the subcortical region; eye anomalies including macular scarring, focal pigmentary retinal mottling; congenital contractures; and marked early hypertonia and symptoms of extrapyramidal involvement.

In terms of the level of risk for birth defects in pregnancy affected by Zika virus infection, the available data shows that among women with possible Zika virus infection during pregnancy, about 5% to 10% of them will have a fetus or infant with Zika-related birth defects. When stratified by trimester infection, as you can see here in this slide, the first column is for the data using the surveillance system from the US states and Washington D.C. and then the last column is for the US territories. When you look at these stratified by infections, the first trimester infection has the highest proportion of infants with Zika-related birth defects.

Other lessons that we've learned during the 2015 outbreak include the different modes of Zika virus transmission. Prior to the 2015 Zika virus outbreak in the Americas, sexual transmission of Zika was suggested by two reports. However, this group of transmission has been supported through multiple case reports from at least 13 countries including the United States.

Zika virus can be transmitted from asymptomatic persons or from symptomatic persons before, during, or after the onset of symptoms. Sex includes vaginal, anal, oral sex and also the sharing of sex toys. As of May 2nd, 2018, 52 cases from sexual transmission of Zika virus have been reported, and this is a small fraction of the total number of Zika cases reported.

However, it is unclear if this is an accurate estimate because it is difficult to enumerate the total cases for sexual transmission in assessing of concurrence mosquito-borne Zika virus transmission. Other modes of Zika virus transmission that have been highlighted during the most recent outbreak was through breast milk. Zika virus has been cultured from breast milk and they have been multiple case reports describing possible Zika virus transmission from breast milk. However, these cases have not been confirmed. And right now, we're just saying it is possible.

Now that we've gone through some of the lessons learned about Zika from the most recent outbreak, including the effects of Zika virus during the pregnancy as well as modes of Zika virus transmission, I would like to talk a little bit about the current status of Zika virus transmission.

From 2015 to 2017, local transmission of Zika virus has been identified from 48 countries and territories in the Americas. This graph shows data from the Pan American Health Organization or PAHO and includes confirmed and specific cases of Zika reported from different regions over time. As you can see from the slide, a much smaller number of cases have been reported to date in 2017 with most cases from the South American region.

Specifically in the United States, this graph shows the number of Zika virus disease cases reported from the US states and Washington, D.C., by month of onset from 2016 to 2018. The peak occurred in July and August of 2016 and declined over the following four months. Very few cases were reported in 2017 and even fewer in 2018. This trend reflects the overall decline in Zika virus transmission in the Americas. And this change in the epidemiology of Zika virus has indications and implications for the interpretation of test results, particularly serologic tests.

This graph shows countries and territories with risk of Zika virus transmission. Areas with risk of Zika are designated by the purple color. Purple shading of a country doesn't necessarily mean that Zika virus is getting spread across the entire country. It means that Zika virus spread by local mosquitoes have been reported in at least one area of that country. Some countries in purple shading may have had Zika virus transmission in the past, are likely to have Zika virus transmission, or currently have low rates of steady Zika virus transmission. I encourage everyone to visit the CDC website for the most updated information.

In terms of the Zika virus infection in pregnant women in the United States and the US territories, as of May 2018, there were 2,461 pregnant women with any laboratory evidence of possible Zika virus infection, and that's symptomatic and asymptomatic women in the United States and Washington, D.C., with 125 infants and pregnancy losses with Zika-associated or Zika-related birth defects.

For the US territories including Puerto Rico, US Virgin Islands, and American Samoa, there are 4,870 pregnant women with any laboratory evidence of Zika virus infections, of which 175 infants and pregnancy losses with Zika-associated birth defects. Although there is currently not a major Zika virus outbreak that we saw in 2015/2016, as I've shown earlier with the maps and the graph, many areas still carry a risk for Zika virus transmission. And so it is important that health care providers know how to counsel about, evaluate for, and manage Zika virus infection during pregnancy given the severe adverse effects of Zika virus infection and also in assessing of people traveling in summertime and people who are traveling to some areas with risk with Zika.

Very briefly, I want to go over what the definition for possible Zika virus exposure entails. It includes travel to an area with risk for Zika virus transmission, residence in an area with risk for Zika virus transmission, and sex without a condom with a partner who traveled to or lives in an area with risk of Zika virus transmission. Before we delve in the particulars of the guidance, I want to stress the importance of shared decision-making in terms of testing and screening of pregnant women.

This is very important in light of the decline in the prevalence of Zika virus infections and the limitations of the available test. During the process of discussing the decision to test, the health care provider’s clinical judgement is imperative, and the decision about whether to advise testing should be informed by various factors such as length of possible exposure, type and location of the possible exposure, intensity of Zika virus transmission, and location of travel as well as the presence of symptoms, the preventative measures taken, patients' preference and concerns, as well as the jurisdictional recommendation.

We will now go through various clinical scenarios to highlight some of the guidelines. In the first scenario, a patient presents to your office practice and says she really wants to go to the beach on vacation and what she should be cautious about. First, the cornerstone of CDC's recommendations is that pregnant women should not travel to areas with a risk with Zika virus transmission.

If she must travel to, or in another situation, she lives in an area with Zika, she should first speak with a health care provider and strictly follow steps to avoid mosquito bites and to prevent sexual transmission. In addition, the use of condoms consistently and correctly during sex or abstaining from sex for the duration of the pregnancy is advised for pregnant women who have partners with possible Zika virus exposure.

Specifically for the travel scenario, the pregnant woman should talk to a health care provider upon return even if she doesn't feel sick. Moving to the next scenario, here, we have a pregnant woman who had traveled to an area with risk for Zika, which in this scenario is Panama. And she reports that she's back and she has symptoms, which as you can see here, includes pink eye, muscle aches, and fever and is worried. So what would everyone … before we go through, what is everyone working through their minds, what will you be considering for evaluation given her travel history, her current signs of symptoms? Evaluation for Zika virus should be considered in conjunction with the tailored recommendation, evaluation.

The current Zika virus interim pregnancy guidance has two algorithms, and here is the image of the algorithm, which you see on your slides. The algorithm on the left is for pregnant women with symptoms of Zika virus disease and the algorithm on the right is for those without. To begin, health care providers should ask about the type and duration of Zika virus exposure before and during the current pregnancy. Knowledge of a pregnant woman's exposure to Zika virus before and during pregnancy is critical contextual information that should be used to tailor pre and post-test counseling and interpretation of test results.

We'll go through some of the limitations of the different types of tests that we have available for Zika virus infection, and you'll see where this information or how this information will be helpful in interpreting the data. The health care provider should also ask about a diagnosis of laboratory-confirmed Zika virus infection before the current pregnancy.

Based on experience with other flaviviruses, previous Zika virus infection is likely to confer prolonged, possibly lifelong immunity. Testing is not routinely recommended for pregnant women with a previous diagnosis of laboratory-confirmed Zika virus infection. For symptomatic pregnant women like this pregnant woman in this scenario, testing is recommended, of course, as soon as possible through 12 weeks after symptom onset.

Once the decision is made to test, the question is what type of test should be performed? What I would like to do is to quickly divert from the guidance to discuss and also to refresh our memory of the types of Zika virus testing that is available. So diagnostic testing for Zika virus infection can be accomplished using both molecular and serologic methods.

Nucleic acid test or NAT is the molecular method and it detects viral RNA in body fluids such as serum, urine, cerebrospinal fluid or CSF, or tissues such as placenta. Serologic tests include the Zika virus immunoglobulin M or IgM enzyme-linked immunosorbent assay to detect IgM antibodies in serum or CSF and the plaque reduction neutralization test or PRNT which measures virus-specific neutralizing antibody titers.

I've mentioned there are many limitations to the Zika virus tests, and we ought to keep that in mind when interpreting both the Zika molecular and serologic assays. And they're listed on this slide. Briefly, since Zika virus RNA in serum or urine are usually short-lived, negative results do not preclude infection, and further testing is recommended, usually by serology test.

Secondly, testing for Zika virus IgM can result in false positive results because of significant cross-reactivity with other flaviviruses such as dengue. Zika virus IgM can persist beyond 12 weeks in some infected people making it difficult to determine the timing of infection. So sometimes the detection of IgM may not always indicate a recent infection. Testing for Zika virus IgM may yield false positive results depending on the timing of exposure in relation to when the test was performed.

Last, PRNT may not distinguish the type of infecting virus in people previously infected with or vaccinated against a related flavivirus. Now, moving back to this clinical scenario into the guidance, so question is what test should be performed? And for symptomatic pregnant women like this patient in this clinical scenario, the recommendation will be for concurrent testing with the nucleic acid test, that's the NAT, on serum and urine and serology IgM on serum.

Once the results for both tests are released, given the time limit today, I'm not going to be going into the different permutations and how to interpret the results in the MMWR that was released last year in 2017. We have a table on the interpretation for the different combinations that I recommend you refer to. As well, we also have an online widget which we'll through that can also assist.

Switching gears to discuss the recommendations for asymptomatic pregnant women with possible Zika virus exposure, the testing recommendations for this population differ based on the circumstances of possible exposure. I'm trying to annotate here. On the right side, the right arm of this algorithm, it contains guidance for testing asymptomatic pregnant women with recent possible exposure to Zika virus, but without ongoing exposure.

For this population, testing should be considered using a shared decision-making model, one in which patients and providers work together to make decisions about testing and care times based on patients' preferences and values, clinical judgment, and a balanced assessment of risk and expected outcomes, and the jurisdiction recommendation.

In assessing the decreased prevalence of Zika cases and to reduce the possibility of false positive results and assessing of the lower pre-test probability, testing is not recommended. Jurisdictions may recommend testing of asymptomatic pregnant women for clinical decision-making or as part of Zika virus infection surveillance.

Now, moving to the left arm of this algorithm, which is for asymptomatic pregnant women with ongoing possible exposure, and ongoing possible Zika virus exposure is defined as those who reside in or frequently travel to an area with Zika virus transmission. Testing for Zika virus should be offered to these asymptomatic pregnant women.

And then Zika IgM testing is not recommended because of the emerging data that indicates challenges in determining whether positive results represent an infection that occurred during the current pregnancy versus prior to conception. We encourage health care providers to continue reporting laboratory-confirmed and symptomatic cases of Zika virus to their local, state, or territorial health department.

Now, let's briefly discuss CDC's guidance for infants who have possible congenital Zika virus exposure. So Zika virus identification and follow-up care of infants born to mothers with possible exposure to Zika virus during the pregnancy is critical, and can ensure that appropriate interventions are available to affected infants. Data from 2016 showed that one in three babies with possible congenital Zika infection had not report of Zika testing at birth.

At the time of the report, approximately one in four babies with possible congenital Zika infection were reported to have received brain imaging at the time of birth. So it is very important that all of you as well as the facilities and the systems in which obstetrics and neonatal pediatric management take place, you all play a critical role in evaluating and managing pregnant women and ensuring that relevant data is communicated to the pediatric providers.

Conveying that information is very critical because the recommendation for the initial evaluation of the infant includes comprehensive physical examination, a standard newborn hearing assessment with the use of ABR. And then what is pretty unique for the Zika virus evaluation, which is not routinely done, is depending on the initial evaluations, doing a neural imaging as well as the ophthalmology exam and the Zika lab exam. This is usually based on the results of the standard of the evaluations as well as the mom's lab results.

In terms of breastfeeding, although Zika virus has been identified in breast milk, the benefits of breastfeeding outweigh the risk of Zika virus infection from breast milk. As I also mentioned, although there are some case reports suggesting, it hasn't been confirmed and has many limitations. And so transmission of Zika virus through breast milk has not been confirmed. In light of all of this and in light that the long-term effects of post-natal Zika virus infection remains unknown, but we haven't seen adverse outcomes. They haven't been case reports of adverse outcome of post-natal Zika virus infection. CDC encourages mothers with Zika virus infection or at risk for Zika virus infection should breastfeed their infants.

Switching gears to CDC's guidance for non-pregnant women of reproductive age with possible Zika virus exposure - So for these women, for women and men, who are planning to conceive in the near future, it's recommended that they talk to their health care providers and consider avoiding travel, non-essential travel, to areas with active Zika virus transmission. If they travel, it is recommended that they strictly follow steps to prevent mosquito bites and sexual transmission, and also that they should be aware of the pre-conceptual guidance related to Zika virus exposure. Testing of asymptomatic non-pregnant women and men is not recommended to establish absence of infection. False negative results might be falsely reassuring.

And on the slide, we've listed a couple of reasons and examples and in language, plain language that can be used to convey this information to your patients. And so false negative results might be falsely reassuring that there's no risk of sexual transmission and lead to inadvertent sexual exposure of the fetus to Zika.

The table on this slide shows the suggested timeframe for waiting to get pregnant after possible exposure to Zika virus if they have to travel with sexual exposure. If only the female had possible exposure to Zika, recommendation is to wait at least eight weeks after the last possible exposure or after symptoms before trying to conceive. If it's only the male that has possible exposure, the male or the couple should wait at least six months after last possible exposure or after symptoms onset before attempting to conceive. This recommendation, the six-month recommendation applies also if both the male and the female had possible exposure to Zika. So really, it's waiting the longest amount of time based on who is exposed.

Since the last update of this guidance on October 7, 2016, additional evidence relevant to the assessment of risks for sexual transmission of Zika virus infection has been reported. Just to highlight, because I know I've gone through a lot and so you guys might be multitasking, so this is the one area I want everyone to be listening to because this is really one of the newer areas that will lead to a change in recommendation. Since the last update of this guidance, we've had additional evidence relevant to the assessment of the risk for sexual transmission of Zika.

Most recently, Paul Mead et al. published the largest core study to date in the New England Journal of Medicine. The study followed 184 men with confirmed symptomatic Zika virus infection from whom serial semen samples were collected through mailed submissions. The study showed that Zika virus RNA shedding declined dramatically during the first three months after illness.

As shown in the graph on the right-hand side of the slide, the estimated meantime to clearance of Zika virus RNA from semen was 54 days. At 91 days or longer after illness onset, 7% or fewer had detectable Zika virus RNA. Detection of infectious Zika virus particles was rare and limited to a few samples collected within one month after illness. Similar findings to Paul Mead's et al. paper have been observed in smaller cohorts, and although RNA has been detected in semen for as long as up to 270 days after symptom onset, detection for long periods is really rare. Thus, we are currently reviewing the data and reevaluating our guidance with a plan of releasing updated guidance soon.

For those women and men with ongoing exposure to areas with risk of Zika, we recommend and encourage them to discuss their reproductive life plan with their health care providers in the context of the potential of ongoing Zika virus exposure. Health care providers should review factors that might influence pregnancy timing as well as the risk for Zika virus infection during the periconceptual period and during pregnancy. For couples who choose to conceive, health care providers should stress the use of mosquito bite prevention strategies while attempting pregnancy and also during pregnancy. For couples who decide to wait to attempt conception, health care providers should talk about strategies to prevent unintended pregnancies.

In closing, I would like to highlight some of the tools CDC has developed for health care providers and their patients. These materials for patients are available on the CDC website in a variety of languages. They help translate CDC's clinical guidance into tools for use in a clinical setting. In addition, CDC has developed an interactive algorithm that allows health care providers to input information about patients' possible Zika virus exposure, the present symptoms to determine whether testing is indicated, when and the type of testing, as well as to help with the interpretation of the test results.

Our understanding of Zika virus continues to evolve. And although we have learned much about the association of Zika and poor pregnancy outcomes in a short amount of time, many questions remain. All of this work is the work of many people. It has been a privilege and honor to have the opportunity to work with so many committed individuals and partners. Thank you all for participating in this webinar.

Moderator: All right. Thank you Dr. Oduyebo for the excellent presentation. At this time, we're now joined by Dr. Carolyn Gould, medical epidemiologist in the Arboviral Diseases Branch of the Division of Vector-Borne Diseases [revised] at the CDC. And we'll open up the line for questions. You can submit a question by using the question block on the bottom of your screen. At this time, we have no callers in the queue, so we can take some of those questions that came in through email while we wait and see if anybody queues up for questions by phone.

Dr. Oduyebo: All right. So that's my cue for the questions. We've received two questions so far through the textbox. The first question is by [attendee]. Forgive me if I've butchered your name. Thank you so much for your question. The question reads, "When a clinician-patient decision-making deems testing is prudent, is there an idea whether or not insurance will pay? If not, how expensive are these tests?" So coverage of testing will most likely depend on the insurance provider. According to our discussions with CMS, for those with Medicaid coverage, testing will be covered as long as deemed medically necessary. The cost of test, what we've heard, can range from $200 to $800. But I encourage everyone to reach out to the insurance to be able to get the exact amount. And testing recommendations, cost, and coverage, just like a lot of other things like plans differ by jurisdiction. I'm going to stop there and see if Dr. Carolyn Gould has anything to add to that.

Carolyn Gould, MD: No. I don't have anything to add to that. Thanks.

Dr. Oduyebo: The next question is from… I'm sorry, I can't pronounce your name but from a yahoo.com. And the question reads, "To determine whether a pregnancy is affected by Zika or like the congenital Zika syndrome, is there serial ultrasounds for BPD, head circumference, etc.? How often for mother's satisfaction?" Thank you for that question.

The recommendation is for close monitoring of the pregnancy, and that includes what we still say, serial ultrasounds, right now, places with different jurisdiction and institutional protocol, the frequency differs. We've been looking at the data to try to see if there is … if we can find information of what the interval should be. And so far, we haven't. We've seen from maternal infection to the detection of abnormalities on ultrasound concerning for congenital Zika virus syndrome as early as about three weeks, four weeks to as long as about 16 weeks.

And so right now, we're still evaluating the data. So we don't have a hard and fast rule. But most places, do serial ultrasounds similar to what is done when other people have comorbidities like diabetes, hypertension where they do it every four to six weeks. In doing these scans, anatomy scans, really looking at the … Since we know that Zika virus infection causes predominant neurologic damage, is looking at the size, circumference, the BPD head circumference. Also doing a really good neuroanatomy, looking at the growth where we've seen arthrogryposis or looking at the names and doing a thorough exam.

I have another question from [attendee]. “Why is there such a decline in infection rates from 2016 to 2017?” Based on that question, I'm presuming you are asking in terms of the graph that I showed in the Americas and also in the US. I'm going to see if Dr. Carolyn Gould can take a pass at that question first.

Dr. Gould: Sure. Well, when Zika virus entered the Americas initially in 2015 or slightly before that, there really was no population immunity at all. So it really spread like wildfire initially with a very large outbreak in 2016. As a result of that, there did develop a certain degree of population immunity. And there have been estimates based on blood donor data, for example, in Puerto Rico that demonstrated infection rates in the 20-30% range.

So probably population immunity was the main reason that the transmission declined so rapidly. Although, we don't know exactly why the infection rates dropped so dramatically given that there wasn't … The majority of people did not appear to be infected in most areas. But population immunity is the primary reason and we expect to see some areas. And what we saw in 2017 was that there were some focal areas of transmissions in some countries actually in Central and South America that actually experienced more transmission in 2017 than in 2016 where Zika was introduced later. And so we expect that to happen in the future. There may be focal areas of transmission in certain areas, certain countries, and certain regions within countries that weren't exposed initially during the large outbreak. But we don't expect to have the degree of transmission that we had in 2016 in the near future because of the population immunity.

Dr. Oduyebo: Thank you so much Dr. Gould. The next question is from [email address] and the question reads, "Was microcephaly always present in neonates that were infected? Or any abnormality may be singular?" From the data and from what we've seen so far, microcephaly, in the beginning of the response, that was really how we knew it was... That was the impetus to starting investigations where we were hearing a lot about the microcephaly incidents in Brazil and in other countries in North America.

But we've been looking at the data from the registries and from the case core studies, well, what we're seeing is that microcephaly is not pathognomonic for congenital Zika virus syndrome, that some infants at birth may have a normal appearing head circumference but have brain abnormalities, which is one of the reasons why neuroimaging modality is recommended for the evaluation of infants with relative concern for congenital Zika virus exposure.

We've also seen some infants with normal head circumference at birth then having post-natal head circumference microcephaly. There's some discussion that sometimes the infants who have congenital Zika virus syndrome have normal head circumference at birth because they also have hydrocephaly, given that they don't have the destruction in the cerebral cortex and that gets filled with fluid. The next question is, "Any abnormalities may be singular?” Most time, what we see is that there is a combination of any one of those five patterns that I discussed makes up congenital Zika syndrome. However, it is not… I wouldn't say it is rare or surprising if an infant has only cerebral atrophy. But usually, it's always multiple.

Next question from [attendee], "Good morning to you. Please advise what to tell patients and couples about demanding testing despite our recommendations to not travel or to postpone family planning? Many people think they can have testing because it's available. But still, if they get tested, they can continue family planning because they will have results that confirm they're negative.” Zika virus testing, as you highlighted, we don’t recommend it. It's not recommended because of that false reassurance. It's definitely a very difficult place for them to be given that there is this available test. They've had these exposures. Why we don't get tested?

But as mentioned, really giving the limitations of the testing, given that they are in a short-lived, the IgM as well, you have to make sure you time it around the right time. And sometimes people's exposure is not necessarily clear. There have been cases where the RNA disappeared from blood system, IgM has disappeared from the blood systems, but we can see the infectious particles in the semen, and there isn't a test for semen.

And so that, you can imagine that situation, that can inadvertently lead to a fetus getting exposed to Zika virus. And so I think you're right. It's a tough position to be in. It's really about counseling. But in the end, after we are able to have a frank discussion with our patients in weighing the benefits and risks and so forth, and hoping that they make the appropriate decisions that fit them in a situation with all of the information.

Next question by [attendee], "Why …?" I'm sorry. Before I go to the next question, Dr. Gould, did you have anything to add to that question by[attendee] about the testing of asymptomatic pregnancy?

Dr. Gould: No. I do agree with your response. The positive predictive value is so low in this population. If you get a positive result when testing isn't indicated, it's very likely to be a false positive and that can really lead people down a course that is not productive for the mom, the baby, anxiety levels. And so I think testing inappropriately can really cause a lot of problems. So I think it's hard to convey that, I think, to patients in a lot of cases, but in understanding the limitations of the assay and the likelihood that when you test, when the prevalence is very low, the likelihood … When you get a positive result, it's more likely to be a false positive than a true positive.

Dr. Oduyebo: Thank you so much Dr. Gould. Going to next question from [attendee], "Why was an altitude cutoff, 6,500 feet shown on the map of the affected areas?" So just sticking with our … I don't know what they call it. Is it entomologist, Dr. Gould? Those who deal with mosquitoes, study mosquitoes?

Dr. Gould: Yeah. That has to do with the range of the Aedes aegypti vector, generally, the studies that have been done looking at the elevation limits for Aedes aegypti proliferation are at a certain level above sea level. And that has to do with the climate and the level of humidity, of water, temperature, and things like that. So when you get above that level, the Aedes just aren't present.

Dr. Oduyebo: Thank you Dr. Gould. Right now, there isn't any additional question online. Do we have any questions by phone?

Moderator: We still have no callers in the queue at this time.

Dr. Oduyebo: Thank you. We have a question from [attendee]. So she asks, "In areas when there is already high population immunity, i.e. Southeast Asia, are the risk of US women traveling to these areas any less?" Dr. Carolyn Gould.

Dr. Gould: Well, you've really hit on the topic of a lot of discussion in terms of country classifications. So there are ongoing discussions by the WHO in collaboration with ECDC, the European CDC and CDC. And right now, we don't have … Because the level of surveillance or the methods of surveillance really vary quite a bit from country to country. And we don't have a lot of data on seroprevalence in terms of knowing what the population immunity is in various areas.

We're not able to stratify, risk-stratify, countries by risk at this point or regions within countries. So the country classification system is currently under discussion by WHO, and there may be changes made to really reflect the fact that we don't have necessarily great surveillance data from all countries. There's no way, at this point and I think in the future, as we move forward with these country classifications, to really stratify risk.

I think when the outbreak was going on in the Americas, there certainly was a concern that there was high risk in many countries. But now that the prevalence has really decreased and transmission has decreased substantially, the risk is likely quite a bit lower. But again, they don't stratify risk by country, so it makes it difficult to provide specific guidance to women who are going to various countries. That's why CDC's recommendations currently don't provide that level of detail because we just don't have the data to do that at this point.

Dr. Oduyebo: Thank you Dr. Gould. And this ties to our next question from [attendee], and the question is ,“what do you see for the future of Zika infection as far as potential changes in the vector or in host population immunity?”

Dr. Gould: I think as far as the predictions that have been done based on modeling, I touched on this before, is we don't expect to see large outbreaks in the near future in the Americas because there is a certain degree of population immunity. But we do expect to see some degree of transmission in certain areas. There may be smaller outbreaks and focal outbreaks in certain areas that maybe didn't see Zika previously. But certainly, the number of travelers who come back with Zika has declined substantially, and the likelihood of local transmission in the US has also declined because of that. But Zika has been quite unpredictable to date, so it's hard to say anything more specific than that at this point.

Dr. Oduyebo: Thank you Dr. Gould. Next question is from [attendee]. “I work in an STD clinic. Should we add recent travel of patient and partner and be counseling accordingly?” I would say yes, I encourage you to do, not even only for Zika but for other emerging infections as we've seen over time from the H1N1, next was Ebola, and so forth, is that there most probably will be another emerging threat sooner or later. And so it is important that travel history should be included routinely. And I think that's something that ACOG also recommends as well. Then now given the summer season with mosquito season and so forth, yes, definitely include these symptoms for Zika specifically and counseling accordingly will be highly encouraged. Dr. Gould, anything to add?

Dr. Gould: No, nothing to add to that. Thank you.

Dr. Oduyebo: Thank you. Next question is from [attendee]. “What are some good ways obstetricians can communicate the mother's testing results with the pediatrician?” CDC would have tools that we're currently in draft form, they'll be released soon, that can assist with the clinician communication, particularly obstetrician to a pediatrician.

One of them that I would just like to highlight is the health card, where it contains the patient's information like exposure of Zika during pregnancy, what the test results are. That could be handed off to the health care provider. Talking to other systems, some people have created different linkages within their electronic health records where the maternal health results for Zika auto-populates in the ped’s. However, that entails that the woman is within the same health system throughout her pregnancy as well as care for the infant. And so there are some limitations to that. And so if you go to our website, I believe in a couple of weeks or so, we should have those tools out. And we will definitely send the links out to ACOG so that that is disseminated to everyone.

Next question is by [attendee]. "There was initial talk of increased Guillain-Barré with Zika. What is the latest on that?" Yes, Dr. Gould.

Dr. Gould: I was just going to say there have been many studies that have indicated an increase in Guillain-Barré cases in association with Zika transmission in those countries. There have been some case control studies as well that have demonstrated a statistically significant association between Guillain-Barré and previous Zika virus infections. So that association, I think, is pretty well-established at this point.

Dr. Oduyebo: Thank you Dr. Gould. I think the last question has been answered in terms of CME maybe. Any other question? We have two more minutes. So going, going, soon to be gone. While we wait for questions, I just wanted to highlight that the guidance on periconceptual and sexually transmission will be changing soon. And once it does, so please keep a lookout for that. The American College of Obstetricians and Gynecologists will send that information out.

I just wanted to check because that will lead to some change in terms of the counseling potentially, changing of fact sheets. And we will update our fact sheet accordingly so that everybody can easily download that and integrate it with their health systems.

Moderator: All right, very good. And there are no callers in the queue. Any other closing thoughts, Dr. Oduyebo, before we wrap up?

Dr. Oduyebo: No, thank you. I just want to thank everyone so much for listening, and I know you have busy clinic schedule and life schedules and for the very interesting and important questions that were asked. Thank you, Dr. Gould, for joining as well and for ACOG for having this call.

Dr. Gould: Thank you.

Moderator: All right. Thank you very much to our presenters and attendees. If you have any outstanding questions that were not answered today, please contact ACOG's Immunization, Infectious Disease & Public Health Preparedness Department at [email protected]. That concludes today's program. Thank you for joining us and we'll see you next time.