CDC: Zika Virus Confirmed as a Cause of Microcephaly

CDC director Dr. Tom Frieden confirmed Wednesday that the flavivirus known as Zika is a cause of microcephaly and other severe fetal brain defects.

The confirmation is based on an evaluation of available data for potential teratogenic effects. Using both Shepard criteria and Bradford Hill criteria, researchers proved prenatal Zika virus infection has a causal relationship with microcephaly and other serious brain anomalies.

The first set of seven criteria used in the assessment were developed by Dr. Thomas Shepard to assess an agent’s teratogenicity — the ability to cause birth defects. The criteria of proof are:

1. Proven exposure to agent at critical time(s) in prenatal development

2. Consistent findings by two or more epidemiologic studies of high quality

a. control of confounding factors
b. sufficient numbers
c. exclusion of positive and negative bias factors
d. prospective studies, if possible, and
e. relative risk of six or more

3. Careful delineation of the clinical cases. A specific defect or syndrome, if present, is very helpful.

4. Rare environmental exposure associated with rare defect. Probably three or more cases.

5. Teratogenicity in experimental animals important but not essential.

6. The association should make biological sense.

7. Proof in an experimental system that the agent acts in an unaltered state. Important for prevention.

Items 1~3 or 1, 3, and 4 are essential criteria.
Items 5~7 are helpful but not essential.

Shepard criteria summary:

1. The microcephaly and other brain defects observed in infants and fetuses were consistent with maternal Zika infection during first and second trimester of pregnancy. Mothers exhibited symptoms, and/or had infections confirmed by labs, and/or had traveled to areas where Zika was endemic. This criterion was met.

2. Data documenting the location of Zika virus infections and the subsequent incidence of microcephaly in those areas was supported by two epidemiologic studies. But as sample sizes were too small and controls were lacking, this criterion has not yet been met.

3. Cases manifesting with a very specific defect (an atypical microcephaly) or syndrome (a narrow range of neurological defects in tandem with microcephaly) satisfied this third criterion. With Zika infection, microcephalic cases displayed adequate bone tissue and scalp skin production, but ‘collapsed’ due to the disrupted development of fetal brain tissue. This is not common in other microcephalies.

4. An adequate number of cases fulfilled the criteria of rare exposure and rare defect — one example cited was that of a pregnant woman who traveled for a week to areas where Zika was not endemic. She tested positive for Zika during her second trimester, and the fetus displayed brain defects associated with Zika after the infection.

5. Studies for this criteria — teratogenicity in animal models — are still under way. This criterion is not yet satisfied.

6. This criterion is met as the causal relationship makes biologic sense.

7. This criterion does not apply to infectious agents.

The essential Shepard criteria have been met for proof of teratogenicity.

Bradford Hill criteria summary

Of the nine criterion — the strength of association, consistency, specificity, temporality, biologic gradient, plausibility, coherence, experiment (on animal models), and analogy — only two criterion are not applicable or not available. The remaining seven criterion were met in much the same manner as the Shepard criteria 1, 3, 4 were met.

What’s next

A spectrum of additional fetal abnormalities has not yet been fully identified in association with Zika infection. This will become clear once some pregnancies being monitored reach term.

We don’t yet know if Zika virus affects adult neurological tissues; some cases of Guillain-Barre Syndrome (GBS) have been reported in areas where Zika is endemic. GBS has occurred in patients after viral infections where neurological tissues have been affected; it would make biologic sense for there to be a causal relationship between Zika and GBS. However, GBS has occurred in patients long after an initial infection, making it difficult to see obvious relationships without further screening and testing.

A Zika vaccine may be some time off; of the flavivirus family, only yellow fever and a couple of encephalitis viruses have vaccines while others like West Nile and dengue do not.

Mosquito control varies widely from state to state, let alone by county or municipality. We do not know if it is adequate to ensure Zika’s spread via Aedes aegypti and Aedes albopictus mosquito species is limited. U.S. experience with the spread of West Nile Virus may be informative.

Funding for additional research, education, training, vaccine development and mosquito control, as well as funding increases for birth control are much needed, But the GOP-led Congress will likely avoid this issue during the remaining days it is in session this election year.

In the meantime, if you’re around mosquitoes in warmer areas of the U.S., are pregnant, plan to be pregnant, or might get someone pregnant, check the CDC’s guidelines on Zika.

9 replies
  1. bloopie2 says:

    One thing that strikes me when reading the CDC materials is the statement that the Zika virus was first detected in 1947 (almost 70 years ago) and the first human case in 1952 (more than 60 years ago). So, for all that time, someone has been paying health professionals and researchers to learn about, and keep track of, this one particular virus (among, presumably, hundreds or thousands of other infections). But for all that time, there was no ‘big’ threat. And now, the knowledge gained so long ago is paying off. Example 1 to trot out when some government cheapskate somewhere questions why we need to fund such work.

  2. bloopie2 says:

    The CDC says this: “Once a person has been infected, he or she is likely to be protected from future infections.” Does this mean that it might even be a good idea for a woman, who absolutely knows she will not be getting pregnant soon, to travel to a Zika area now? Silly thought, but still … there is no vaccine yet.

  3. Rayne says:

    bloopie2 — Yes, the 1971 research I noted yesterday is particularly important. Scientists already had clear evidence that Zika caused damage to neuro-tissue. It will be very important to study the evolution of the virus; what made it more aggressive than it appeared in previous outbreaks? Or did evidence of birth defects and other Zika-caused damage go unreported/unrecorded?

    Which brings me to your point about unpregnant women (or even men who may potentially distribute the virus during sex): we do not know enough about Zika’s affects on adults. Cases of Guillain–Barré Syndrome have been reported. Mortality rate for GBS is fairly high at 1-in-20; no information yet about mortality for Zika-caused GBS. I wouldn’t risk it if I were still of childbearing age — and I certainly wouldn’t risk it if I were immune compromised.

  4. lefty665 says:

    Thanks for the post. Zika sure looks like it does bad things to fetuses. That makes it like other viral and bacterial infections, and everything else that causes inflammation and stress during critical periods of fetal development.
    However, several of the criteria above are “consistent with”, “traveled to areas”, “not supported by epidemilogical studies”, “studies not completed”, “relationship makes sense” and a couple of tautilogical statements.
    That’s not much in the way of actual scientific evidence “proving causality”. I expect we will get the evidence, but this ain’t it.

  5. Rayne says:

    lefty665 (9:42) — In re criteria: That’s why both Shepard and Bradford Hill standards of proof rely on multiple criterion for proof of causality. Researchers observed the virus actually attacking neuro tissue:

    … That Zika might wreak havoc in fetal brains isn’t all that surprising, given the virus’s effect on mice and the neurological problems sometimes observed in infected adults, says Carlos Marcondes, an entomologist who studies disease-carrying insects at the Federal University of Santa Catarina in Brazil. In lab mice, Zika virus makes a beeline for the brain. “It causes serious damage,” Marcondes says. Nerve cells break down and brain tissue softens. …

    [source: Science News]

    A 1971 study also noted similarly damaging effect of Zika on neuro tissue. Add this to the incidence of highly specific microcephalic traits among births to women who tested positive for Zika AND lived/traveled to the same areas where Zika was endemic, in addition to the rare exposure/rare event criterion cited. Researchers have also found the virus postmortem in neuro tissue of fetuses which displayed defects matching the spectrum of neuro damage attributed to Zika.

    I recommend reading the CDC’s report — this is the same standard of causality they apply to other infectious diseases and for the CDC proof has been satisfied.

  6. lefty665 says:

    Rayne @10:52 I don’t doubt that Zika is a bad actor, but 45 year old studies with no current follow ups? Really? That’s tens of thousands of viral life spans. Oodles of time for a virus to evolve for better or worse, but for sure it won’t be the same today as it was during Nixon’s first term before Watergate.
    I subscribe to and generally take off of Science News, but thought their Zika article was breathless and overblown when it hit my mailbox. I look to CDC for hard science, not stuff like coincidence, and “makes sense”.
    Thanks for your daily fix, I look forward to it each morning.

  7. Rayne says:

    lefty665 (12:29) —
    1) With regard to proof: I suggest reading the NIH director’s blog post. He mentions:

    (a) NIH-funded research showing Zika infected and killed neural progenitor cells;

    (b) A small study of Brazilian women diagnosed with Zika during pregnancy in Rio de Janeiro displayed a “disturbingly high” attack rate;

    (c) Offered a theory as to why birth defects were not previously attributed to Zika virus.

    He provided links to studies for (a) and (b). These, combined with much more information outlined in the CDC’s report, assessed against not one but two different criteria for proof of causality, assured the CDC of proof.

    Sorry you don’t think this is adequate, but these are the same criteria the CDC and NIH use as measures.

    The lack of urgency in research between that 1971 study and now may be understood by NIH director’s theory about birth defects. If the virus was endemic in areas where many people had acquired immunity, the dramatic uptick of birth defects wouldn’t have been observed (nor a possible uptick in Guillan-Barre cases), thus reducing impetus for research proposals and funding.

    You should note, however, there’s quite a large body of research into flaviviruses during that same 45-year period — flaviviruses including yellow fever, dengue, chikunguya, encephalitis, which are much as they have been during the same timeframe.

    2) With regard to Science News as a source: This outlet was the one which fully quoted medical entymologist Carlos Marcondes. Most U.S. outlets have given him short shrift in spite of his expertise on the subject of mosquito-borne diseases. You want something more authoritative from him besides Science News’ quote? Here, read this pdf (I am even more worried now that I’ve read it, based on the observation about satyrism between Aedes aegypti and albopictus mosquitoes). I suggest doing a search on Marcondes using Portuguese rather than English: Carlos Marcondes, entomologista de medicina, Universidade Federal de Santa Catarina, Brasil

    3) In re Science News’ “breathless” tone: That’s how the CDC’s primary deputy director Dr. Anne Schuchat sounded when she said Zika was “scarier than we initially thought.” The CDC is very worried based on the *new* information they have about the virus; I hope you take that away from NIH director Dr. Francis Collins’s blog post, if you didn’t come away with that from Schuchat’s presser statement. The epidemic-level number of cases and the recent emergence of microcephalic cases now demands more action wrt vaccine, especially since the Olympics this year in Brazil will expose a much larger number of overseas visitors to endemic Zika which they may carry back home.

    You might also compare the NIH director’s most recent blog post to this one from January this year. The tone has changed.

    4) You’re welcome. It’s a labor of love. Or sickness. Or obsession. I get them confused. LOL

  8. lefty665 says:

    Rayne @ 2:09 Thanks for the additional links, I’ll look at them when I get a little time. An upcoming gig and finishing our taxes are higher on my list at the moment.
    I’ve never doubted that Zika can do bad things. Most everything that gets into early fetal development does.
    A lot of the Brazilian and other SA reporting showed a profound lack of rigor, right down to the inability of the medical community to correctly diagnose microcephaly, and patient self reporting of mostly vague and mild historical symptoms that may have been Zika (or not). Pesticides introduced in local water supplies to combat mosquitoes further muddied the causality waters.
    I listen to virologists, microbiologists and epidemiologists from places like NIH and CDC when they present hard data that comes from their labs and research. Administrative press statements and blogs can be more PR related and less scientifically reliable. Their relationship to underlying science may be casual. We saw that with CDC and Ebola.
    I only know two people with fluency in Portuguese. Neither will be inclined to be pressed into service as translator, so that’s not likely to be very useful to me.
    Re 4), Differentiation among them can be level of intensity as much as anything else, making them easy to confuse. All may exhibit pathology, as can fandom. LOL back atchya. Have a good one.

  9. Rayne says:

    lefty665 (3:44) — You’re really just being difficult. :-)

    I didn’t ask you to speak/read/translate Portuguese, I asked you to search using the Portuguese. Copy this and paste into search engine query line: Carlos Marcondes, entomologista de medicina, Universidade Federal de Santa Catarina, Brasil

    And then note what comes up. Very different results from English language search, though the results are overwhelmingly in English language if you have your browser & search engine preferences set for English. I also used Google Translate to create that query.

    I don’t think Brazilian & SA outlets were that far off in their reporting; their work looks validated after NIH research, which may suggest a colonialist attitude toward disease.

    I think it was very easy for anti-pesticides/anti-Big Ag/anti-Big Chem to use this as an opportunity to make their case look better. This is not the right case, because decades of exposure do not produce these symptoms elsewhere. They do produce other problems like bee die-offs — and this open application of the Shepard + Bradford Hill criteria offers an example of how to make a better case for proving chemicals=bee die-offs (i.e. prove criterion 7 in Shepard criteria.)

    It was also a method for anti-tax neoliberals and pro-Olympic/pro-corporate sponsors who don’t want to pay for research or mosquito control to inject doubt into this crisis. So much easier to cast aspersions on Spanish+Portguese language media.

    NIH and CDC have had data, but now have enough data for causality, AND they included the research in their blog and press statements.

    Enjoy the rest of tax season.

Comments are closed.