Zika in Pregnancy: Epidemiology and US - HD

Introduction and Disclosures

Okay, Zika, what is the current buzz?
Let me see if I can go forward here.
It's not, is it working?
There we go. My little mosquito.
Okay, so my disclosures, I have nothing
to disclose financially,
however, I do feel full disclosure, I am not a Zika expert.
I am helping out here.
They needed a Zika speaker, and so here I am.
I did do some consulting for a Dr.
Karen Sohan, where she was working in Trinidad, Tobago.
They had an epidemic there.
She's an obstetrician,
and they were looking for someone to help them
before they were recommending termination.
So I have a lot of the cases from Trinidad and Tobago
to show you epidemiology, constantly changing care.
Even in your syllabi
that were just due two months ago, most of it's outdated.
They update these numbers almost every month.
And so the current lecture I'm showing you today, some
of these numbers I updated in the last two days,
you can always go to the CDC website
to get the most current numbers.
The Pan Am Health Organization also has a lot
of informative data and current numbers for you.

Lecture Objectives

So our lecture objectives, we're gonna review the virus,
including the vector transmission symptoms,
the current stats and trends.
I'm gonna provide an update for the CDC recommendations
for testing and travel.
And then probably what most of you are here for is
to identify the ultrasound findings
of congenital Zika syndrome.

The Virus

Now, the virus, most of us never even heard of Zika
until about three years ago, but this is not a new virus.
It's been around since actually the late forties,
early fifties, first described in Africa, there is an Asian,
lineage of this virus that
multiple mutations must have occurred that somewhere
after about 2007, it started being associated
with neurological complications.
And that is the virus
that we have seen in the Americas since 2015
that is causing all of these recent problems.

Vector

Now, the vector of the virus is the 80 species of mosquito.
There are two types, the Egypt, the gti,
and the elbow pictus.
These mosquitoes do not only transmit Zika,
but dengue and chicken.
I cannot say that one. Chiia
and yellow fever, as well as other viruses as well,
they tend to like warm climates, low altitudes.
They lay eggs near standing water like other mosquitoes do.
They can bite during the day and night.
And what's important to know
that these mosquitoes can only travel about a
half a mile to a mile.
So when we talk about Zika coming to the us,
it's not like they're flying 4,000 miles from
from Brazil to get here.
Okay? It's the humans that are bringing it over.
Now does that mean we have to worry about it?
Well, these mosquitoes are here in the US
and this is the most recent map from the CDC website,
from the end of September,
showing you these aren't actual numbers of mosquitoes
or actual locations of the disease,
but if the virus was here, where it could potentially spread
to, because again, it likes these conditions
and these is where these mosquitoes have been reported.
We particularly wanna look at the blue colors
because this is where the Egypt mosquito tends
to like, and that's the one
that prefers humans and biting humans.
So that's the one we have to be careful about.

Transmission

Now, transmission, as I mentioned,
typically it's gonna be a human that gets bit by a mosquito
that bites other humans and yada yada.
This goes around and around.
There are other ways that we can get Zika,
through pregnancy from mom to fetal transmission
through sex, through blood transfusions.
Theoretically we can get lab acquired infection as well.
There's only been one reported case in the US from a lab
acquired infection.

Symptoms

However, the infection itself symptoms are very similar
to other types of viral syndromes.
Kind of the pathognomonic features
for Zika in particular are the rash and the conjunctivitis.
The conjunctivitis will look a lot like pink eye.
The rash in particular tends to be these very small papules.
They cover large a areas and it does not itch.
So that is something to pay attention to.
Typically, the symptoms will begin about two
to seven days after exposure.
They'll last for a couple days to a week,
and note that only about 20% of people
that are infected will actually experience some symptoms.
So most importantly, 80% will not.
Now whether or not you have symptoms
and express those symptoms
or not, once you are exposed,
you are considered immune for life.
Now, the infection itself is not really that bad.
It tends to be fairly mild.
And so some potential consequences might be hospitalization,
but that's very, very uncommon.
Death is exceedingly rare.
There's only been 20 total cases of deaths,
in all of the Americas.
And only one case in the US that was in Utah happened
to be an elderly patient.
It was acquired abroad,
and for some reason, his viral load was a hundred
thousand times higher than the average seen in other infected person.
So that was just kind of a really rare, rare case.

Potential Consequences

Guillain-Barré Syndrome

Other potential consequences we've all heard
of Guillen bere, tends
to be more common in adults and in males.
And this is kind of where it's a super aggressive.
Your immune system kind of takes over.
And so once it gets activated by the virus,
it now starts attacking your own peripheral nerves.
Tends to starts in the legs, moves up
to the arms in the face,
and it affects the chest, can cause breathing difficulties,
outcomes, most people will recover fully,
but it can result in near total paralysis
and does have about a three to 5% mortality rate.
Total numbers in the US from Zika related Guillain bere are
just about 15 and 52, including the US territories.

Congenital Zika Syndrome

Congenital Zika syndrome are the one that we hear the most about.
These are the birth defects that involve the both central
and peripheral nervous system, the eyes, the joints,
the reported risk of getting the syndrome once the mom is
infected with the viruses only about 1%.
I think that's important because I used to think that,
oh my gosh, once mom tested positive for Zika virus,
that all of these fetuses would be infected.
However, it's only really about 1% that risk
of the fetus being infected and
or having consequences is gonna be increased if the mom happened to be symptomatic
and if that exposure was earlier in pregnancy,
which makes sense to us because
that's when embryogenesis occurs.
However, note that that risk is not restricted
to just the first trimester.
This was an interesting paper published in the Lancet,
that was looking at the baseline prevalence of microcephaly,
in neonates,
and then with timing exposure in the first, second,
and second and third trimesters.
And we noticed that while the risk ratio goes down,
it still exists if they were exposed in that second
or potentially second, third trimester.
So it can, it's not just with that first trimester.

Epidemiology

So epidemiology, I feel like rissole
and say, let's do the numbers right.
So epidemiologic update in the Americas, you will see
that the lighter yellow colors are where it was kind
of they first occurred.
That was back in 2015.
The darker colors are more the countries
where we had more recent infections going on.
Good news is there have been no additional countries,
or territories since epidemiologic week 44.
So that's about November of 2016.
No new countries have been reporting Zika,
at least in the Americas.
Looking at the overall numbers, again,
this is different from your syllabus
because this was updated yesterday.
We have now about 48 countries where they have the mosquito,
born cases about five countries
with sexually transmitted cases.
In your syllabus it says 26,
and we now have 27 countries
with the congenital Zika syndrome.
Guyana was the most recent country to be added to that.
These are the total number of confirmed cases,
about a quarter million, so far in about,
close to 3,700 of the Zika syndrome.
While those numbers seem high,
if we look over the course from 2015,
and here we are in 2017, we know
that there is an over a marked overall decrease
in the number of cases.
So we are on a very good trend of decreasing numbers,
with the exception is that in Central America, Costa Rica,
is actually increasing as well
as there's some specific regions in South America.
I wanna point those out. Noticing again, here is 2017.
So to make this a little bit bigger, Bolivia, Ecuador
and Peru as well as Argentina,
those particular countries are actually seeing a rise in
their own country's numbers of the Zika virus
here on the homeland.
These were the states that had in 2015
that had reported cases of Zika.
You'll notice in California,
and most of those were travel related from Mexico that we had only about 61 cases in the mainland
of the US in 2016.
We were up to over 5,000 cases that you can see again
with the dark blue numbers.
But here we are in 2017.
So again, these numbers are decreasing.
Here, I've kind of broken it down by year 20 15, 16
and 17 from the mainland and the US territories.
We will look again for this year.
Most all of these, at least in the US, are travel related.
This one case that is los local mosquito borne,
again, just got in the literature somehow in the last couple
weeks since your syllabus was published there.
And most of the cases in the US territories are actually
from mosquito-born, so people aren't going
and bringing it to those countries.
Most of our cases here were from last year in 2016.
That was that one laboratory acquired case
that I was talking about.
And the local mosquito-borne cases, those 224 cases,
almost all of those, in fact, all
of those came from Miami-Dade, Florida
and Brownsville, Texas.
So most of those 218 were from the Miami-Dade
County in Florida.
This is a map of where they of where that location is.
As of June of this past year, June 2nd,
the caution travel advisory has actually been lifted.
They do recommend though, that if you live there
or travel too that you want
to practice mosquito bite prevention, use condoms,
and if there was any possible exposure
between this time period when it was first reported on
August 1st, 2016
and June 2nd of this year, anyone
with symptoms should be tested.
And those planning to conceive should wait.
Women should wait about at least two months
and men's six months
because the virus is believed to last longer in semen
actually than it does in blood.
Now in Brownsville, Texas, there's only been six cases.
And again, this is new in your syllabus.
That was still there was an advisory travel caution,
just a couple weeks ago when the syllabus was due.
But now, very recently, they have lifted that
with the same exact cautions if you happen
to live there or travel there,
or perhaps in that last 10 months that you should wait.
If you're planning to conceive.

Outcomes in Pregnant Women

Now some more numbers regarding outcomes of pregnant women
that have lab evidence of Zika infection.
Again, this is in the mainland and the territory.
They're looking at total cases,
and then completed pregnancies
with birth defects, with or without.
And then how many live born or pregnanc?
So basically this is even less than the 1% risk, right?
And that's because a lot
of these are terminating when they see, when they hear
that they have laboratory evidence,
which is really unfortunate.
It's been about a 15 to 25% termination rate.
So that's why those numbers are a little bit lower.

Testing

So testing how, who and when.
The main way that we first started testing for Zika was
with this NAT test, which is the testing
for actual Zika, RNA.
And that can be found in the serum urine
or an amniotic fluid.
It can be positive within about the first two weeks following the onset of symptoms.
The bad news is that a negative test does not exclude Zika virus IGM, which is serum.
So that's your antibody response to the virus.
Typically will be positive within the four to 14 days after exposure.
It can be positive up to 12 weeks or possibly longer.
So the bad news is it cannot determine the timing
of infection prior to the current pregnancy.
So again, you can have those antibodies floating
around from potentially maybe you were bit
even six months ago.
Some more specific tests are these radio immune assays,
the PCR and the print tests.
The FDA has issued these for emergency use authorization,
if it's presumed positive
or if there are any sort of equivocal
or inconclusive IGM results.
And they're only distributed to certain qualified labs.
So you'd have to find out from the CDC,
which labs actually have these particular tests.

Who Should Be Tested

Now, who should be tested?
This was recently updated in the CDC, just this past July.
They've come up with four categories of at-risk individuals,
but first we need to define what they mean by
possible Zika virus exposure.
And that is living in traveling to
or having unprotected sex with someone who lives in
or has travel to an area with risk of Zika virus infection.
So our first category is anyone with possible exposure
with symptoms.
So they have to have the symptoms.
Any symptomatic pregnant woman with possible exposure,
any asymptomatic woman with ongoing possible exposure.
And the operative word here is ongoing
because with this most recent update, they said
that if it was not ongoing exposure,
routine testing is no longer recommended.
And prior to this past July, we were testing women,
even if they had not ongoing exposure,
it was a one-time exposure.
You can then go for these symptomatic
and asymptomatic pregnant women.
They have these very nice algorithms on the CDC website.
So I'm showing you the one this would be for symptomatic,
they really paid a lot
of attention saying every single encounter
that a pregnant woman has with her provider, she needs
to be asked, Hey, did you travel to any Zika pot in place
with Zika possible Zika exposure?
Did you have sex with anybody
that had possible Zika exposure?
Because this is really how we want to catch these patients.
So these are the ones with symptoms.
You wanna test them as soon as possible through the 12 weeks after the onset of symptoms,
and they're gonna test with both the Zika RNA
and the IGM
and then there's algorithms what to do from there
with the asymptomatic patients.
Again, gotta ask, gotta ask
because only you know 20% are gonna have the symptoms,
80% will not.
So again, it's only those with ongoing exposure.
They are to be tested three times during pregnancy,
and it's only with the nat with
for the Zika RNA virus.
And then it tells you what to do from there.
The fourth category was pregnant women
with possible exposure
and fetal prenatal ultrasound findings that are consistent
with congenital Zika syndrome.
If you see findings on ultrasound, then you wanna follow
that lab algorithm as if they were symptomatic,
even though they may not be symptomatic.

Ultrasound Protocols

So what do we look for on these exams
and how often do we do them per the CDC ACOG
and the Society of Maternal Fetal Medicine?
They say we should be doing serial exams about every three
to four weeks if there is any sort of evidence
of maternal infection.
And it can also be considered for women who have traveled
to endemic areas and have no evidence of the infection
because we know it can be asymptomatic.
Now, what we see has really been based on observational
studies in the literature since early 2015.
There are no universal Zika scanning protocols
to really optimize sensitivity for these findings.
The International Society of Ultrasound and Obstetrics
and Gynecology did have something saying,
these are the minimum number of images you should get to
identify CNS abnormalities.
But really, I think what's important is to know what to look
for and when to look.
So congenital Zika syndrome involves
intrauterine growth restriction.
We will see in anomalies in all
of these different structures.
Let's start with the brain and skull.
Probably overwhelmingly the most common thing we will see is
cerebral volume loss, evidence of loss.
So that's gonna result in microcephaly,
it's gonna result in enlarged subarachnoid spaces,
calcifications, subcortical, periventricular,
even in the cerebellum ventricular magaly.
And then we're gonna have some other abnormalities
that we're gonna go over as well,
but particularly in the posterior fossa.
Most of the hubbub though, has been
around microcephaly, right?
In fact, I used to think, all I was looking
for when they said possible Zika exposure is I just look at
the head circumference and say, oh, there's no microcephaly.
I'm done. I don't need to look anymore.
So let's talk about microcephaly.

Microcephaly

Microcephaly is actually found in about two
to 12 cases per 10,000 live births in the us.
This would be kind of a typical head size.
This would be a baby with microcephaly
that is considered two standard deviations below average,
and then three, which equates
with about a less than third percentile, okay?
Because that's just how you need to think about it.
It's severe microcephaly.
And once we get three standard deviations below average,
which equates with about less than the one percentile.
Now what we need to keep in mind that the CDC definition
of microcephaly is a postnatal diagnosis.
And as a postnatal diagnosis, it has
to be more than two standard deviations below the mean,
which again, less than the third percentile.
And on the CDC website,
they even have a YouTube video showing pediatricians
how they should be exactly measuring the fetal head
circumference to make this diagnosis.
Now, the in utero definition of microcephaly is really not
as clear because again, it really wasn't defined that way.
But what we do know is that we tend
to under measure the head circumference.
And in this one paper of over 3000 cases, they said
that we underestimated the head circumference measurement
to the actual head circumference measurement
for some reason, particularly in male fetuses.
And when there was vertex presentation in this study
of 20 cases, even when we thought in on ultrasound in utero
that we were somewhere between the two
to three standard deviations
below the mean 90% were normal at birth.
So somehow we're really kind of over calling this
by using these standard deviations.
Now why could that be? I don't know.
I kind of was looking at a case that we had recently
of a third trimester pregnancy that was Vertex presentation.
I thought, okay, well I with the thought
that these were pretty good measurements,
but note how when it's vertex, you kind
of get this dropout at the extremes at
the forehead and the back.
And so maybe really the measurements should be more like
that, but we're only putting around
what we think we can see.
I don't know, maybe that's part of the problem.
The society of maternal fetal medicine in February
of 2016 published a statement about ultrasound screening
for microcephaly.
So not for all of congenital Zika syndrome,
just about microcephaly.
And knowing that we do have this known underestimation,
they said, if we wanna be certain, then we're gonna have
to use more than five standard deviations below the mean if,
and that's a hundred percent like
certainty, like wait, way bad.
If it's more than three standard deviations below the mean,
then we're gonna diagnose microcephaly.
But if it's only two standard deviations below the mean,
then you should probably look for other evidence
that might tell you that Zika syndrome is going on.
So again, we're using a greater standard deviation than they
use to diagnose the postnatal diagnosis of microcephaly.
And they state that if your reporting package only reports
the percentile, which is like what mine does,
then they actually gave a chart that you can go
to on their website so that you can convert that
to standard deviations.
There was this nice meta-analysis that came out in May
of this year that we're looking, they were trying to see,
you know, if we were using three, four,
or five standard deviations, you know,
how well were we at diagnosing Zika virus infection?
And microcephaly note that all of these nine studies, none
of them actually included Zika infected patients.
They were just using other studies
of head circumference measurement.
And while it's true that we'll have very high specificities,
the higher we get away from that standard deviation
and perhaps using two standard deviations, we would capture
all of those fetuses.
We're gonna have a lot more false positives.
So perhaps there's other things we should be looking for.
And thank goodness there actually are,
which is why I really like this paper
that just came out in the Lancet of this past summer.
And it gave really two great take home messages.
The first was about timing of when we see these findings
of their 14 cases.
It was a small group out of Martinique.
They had 14 confirmed congenital Zika virus cases,
four of the 12.
So they had 12 that had ultrasounds early on between 16
and 20 weeks, and they only saw abnormalities
in about a third of those.
And four of the patients, all of those actually terminated.
Two more joined the pool.
They found about 90% they could see of the abnormalities
between 20 and 24 weeks.
Once you got past that, then they could see on our percent.
So their take home message was the public health efforts
should really focus on scanning between 20
and 26 weeks gestation.
I think this is helpful at least knowing that we don't,
if we don't see anything by that time, we don't have
to keep scanning, you know, 32, 34, 36 that we expect
to see something with.
The bad part about this is usually that's
around the time when you can offer somebody an elective termination.
So it's just up against that window.
What they also looked at were the other major brain
anomalies that were identified.
And if we look here from the most frequent to least frequent
microcephaly was only seen about 64% of the time.
So if that's what we're looking for to make the diagnosis,
we're gonna miss a lot of cases.
There's a lot of other things that we should be looking for.
And they stated, they concluded that the assessment of mi of
of just head circumference measurements from
microcephaly is not an effective screening school tool.
We need to look at other things, which brings me back
to this paper in radiology that came out of our colleagues
in Northeastern Brazil where they obviously had a lot of congenital Zika
syndrome going on.
They had 17 confirmed cases, 28 presumed.
And you will see all the different abnormalities
that occurred intracranial again,
volume loss being seen in a hundred percent ventricular
magaly, and so forth.

Other Brain and Skull Anomalies

So now I'm gonna show you some examples.
These were cases from Trinidad Tobago, just showing you kind
of the typical ventricular magaly.
Here are the large subarachnoid spaces, right?
So right here you're just seeing too much space between the
cortex and the surface there.
Here's another example right there.
We're seeing the subarachnoid spaces are too big
and it looks like there's a bunch of junk in there as well,
which was one of the findings that was reported in
that radiology paper,
which they called heterogeneous material in the region
of the confluence of sinuses.
But that that's kind of demonstrating the same thing
that we're seeing right there.
Here's another example.
We're seeing some blood vessels going through there, but
there's all of that material up there.
Here's an example of ventricular magaly
and then some lissencephaly.
So kind of a smooth brain which we see the
major fissures just look too big, right?
It just looks like a really smooth brain.
You can also see poly micro gyre that you see right here
with all those little undulations occurring
that calcifications tend to be cortical and sub-cortical.
They're identifying some over here,
but all of these are our calcifications
that we will see in the brain.
Here's another example.
We have ventricular magaly,
those enlarged extra axial spaces,
and then all of these calcifications.
And here's an example of some cerebellar calcifications.
Now note, these are different than the calcifications than
we tend to see with the torch infections.
Usually with torch, this was a case that I just had
of known CMV infection where we're typically looking in the
caudate nucleus and the thalamus.
So they can occur there with Zika,
but that's not where they characteristically occur.
So just so you know, when they talk about intracranial
calcifications, ortho thal strike calcifications that occur
with CMV infection that we're seeing right here,
those aren't the ones that we're talking about with Zika.
We're looking in the cortex, collosal dysgenesis,
seeing an absent Calum, that colpocephaly that
we saw earlier on the 3D images.
Here's a case of a complete agenesis of the Al Coum
with the teardrop shaped ventricle.
We're seeing these cystic structures,
which is really a dilated third and the interhemispheric
or dorsal cyst, this is an example of porn cephalic
where we just have some destruction of the brain
that's communicating with the ventricular system.
And then some cerebellar anomalies that we're seeing here,
as well as this is an MRI out of
that paper from radiologists showing a very small verus
and as well as a small cervical cord.
And what I want you to also see is this abnormal head shape
and kind of the sloping of the forehead
because the abnormal head shape has also been described
with congenital Zika syndrome.
They tend to have a collapsed appearance,
overlapping sutures
and redundant skinfolds as evidenced by this picture right here.
Here's an example from Trinidad Tobago that
my colleague sent me here,
showing those overlapping sutures.
Craniosynostosis can also be seen.
So it kind of looks, you don't see all those sutures tend
to be closed and they kind of tent up
and kind of peaked up there.
Here's another example from the radiology paper
which on bone windows you can really see those aversion
of the sutures over there.

Ocular Manifestations

Ocular manifestations, I have these in two categories
because these are really the ones
that may be seen on prenatal ultrasound
that you need to be aware of.
Cataracts. I'm showing you what normal lenses look like.
Cataracts are just gonna be really epigenic, right?
And they're gonna kind of fill in those lenses.
Here's an example that I had.
This wasn't a Zika case,
but it was just a case of fetal cataracts
to show you what that looks like.
Small orbits. So if you think the orbit is small,
if you're suspecting it, they actually,
you can measure it from the outer lateral and medial margin.
And there's nomograms that you can turn to, to look for
what is normal club feet.

Limb Manifestations

I'm showing you normal. When we have a coronal image
of the tib fib, we should be seeing short axis fuse
of the knee and the ankle cartilaginous structures.
Here we have the classic club with the foot bent in
that way, and the other foot as well.
Arthrosis is where you're seeing clubbing.
But more than that, you've kind of got the joints.
They don't bend.
They just kind of stay out in this very rigid extended position right here.
And another example, you can even see this in the
first trimester.
Occasionally you can see arthrogryposis
that we're seeing right here.

Treatment and Prevention

Treatment, unfortunately there's no vaccine for this.
This is you can treat the acute symptoms
of the infection with Tylenol, important
that they don't take Motrin or nonsteroidals
because of the increased risk of bleeding.
So prevention is really about avoiding
travel to these countries.
You can go to the CDC website
and it'll actually, you can look at your individual country
and it will tell you what the risk is over there if you have
to travel there or if you happen to be an endemic area.
You definitely wanna protect yourself from mosquitoes.
You use repellent nets for sleeping,
eliminate the standing water outside your home,
and you have yet another reason
to practice safe sex with condoms.

Summary

Okay? So in summary, we know transmission is mostly from
mosquito bites, but it can be these other routes as well.
Good news is numbers are decreasing in the Americas except
for these specific areas.
So if you happen to be traveling there
or your patients symptoms are typically mild.
And again, these death is very, very rare.
The congenital Zika syndrome only about 1%.
So even if the patient tests positive,
only about one in a hundred will that fetus develop
those that syndrome.
You wanna test anyone with symptoms pregnant
with ongoing exposure
or anything suspicious on ultrasound, then we are,
if they have the infection and they're asymptomatic,
but there's travel, you wanna do it about every three
to four weeks with the optimal window being about
22 to 26 weeks.
Probably most important thing I wanna take send home is
that microcephaly is only one
manifestation of this syndrome.
We wanna look in the brain for all of these other things
as well as the orbits for cataracts, club feet,
arthrosis, and IUGR.
If there's no other findings, probably best to use
that more than three standard deviations below the mean, and then five to really be certain.
The CDC, again, you wanna go to this,
it's an invaluable resource.
They keep updating this almost on a weekly basis,
but protection is really paramount.
You really need to take that protectant with you.
So we will get rid of all of our mosquitoes.