Babies
born to Zika-infected mothers are highly likely to have brain damage,
even in the absence of obvious abnormalities like small heads, and the
virus may go on replicating in their brains well after birth, according
to three studies published Tuesday.
Many
types of brain damage were seen in the studies, including dead spots
and empty spaces in the brain, cataracts and congenital deafness.
There were, however, large differences among these studies in how likely it was that a child would be hurt by the infection.
One study,
published by The Journal of the American Medical Association, assessed
442 pregnancies registered with the Centers for Disease Control and
Prevention between January and September in the continental United
States and Hawaii, most of them in returning travelers.
Continue reading the main story
Continue reading the main story
That
report found that 6 percent had birth defects. None of those birth
defects occurred in infants born to women infected in the second or
third trimester.
By contrast, in a study
of 125 Zika-infected women in Rio de Janeiro done by Brazilian and
American scientists and released by The New England Journal of Medicine,
almost half of pregnancies had “adverse outcomes,” ranging from fetal
deaths to serious brain damage.
Of the 117 infants born alive, 42 percent had “grossly abnormal” brain scans or physical symptoms, the authors said.
Other
studies from Colombia, Brazil and French Polynesia have suggested that
brain damage rates are between 1 and 13 percent. But each one uses
different measurements of brain damage and different definitions of
which mothers to include, so the question remains unanswered.
The
women in Rio were first selected for the study because they had rashes,
and all were confirmed by testing for the virus itself, rather than by
less accurate antibody testing.
Several
scientists said the symptoms suggested that the women had more serious
infections and were more likely to have damaged infants.
But
a study author, Dr. Karin Nielsen-Saines of the David Geffen School of
Medicine at the University of California, Los Angeles, said that other
work by her group showed that women with no symptoms could have viral
loads as high as women with rashes. Other studies that used antibody
tests, she said, might have accidentally included women who never had
Zika.
Dr.
Deborah Levine, a professor of radiology at Harvard Medical School,
noted that many of the Rio women had previous infections with dengue
virus, which might have worsened their Zika infections or prompted more
intense immune responses, in turn damaging their babies.
Both
studies showed that only a very small percentage of the babies with
brain damage had full-blown microcephaly, which is defined as a head
size three standard deviations below the mean for the baby’s age.
“This
shows once again that microcephaly is just the tip of the iceberg,”
said Dr. Albert I. Ko, a Yale epidemiologist who has worked in Brazil
for years.
The
Rio study also counters the idea that only first-trimester infections
are threatening. The authors found that 55 percent of first-trimester
infections produced bad outcomes, 52 percent of second-trimester ones
did, and 29 percent of third-trimester ones did.
“You
can’t just say that the first and second trimester are the risk
periods, and the third is not,” said Dr. Roberta L. DeBiasi, the chief
of pediatric infectious diseases at Children’s National Health System.
In the third study,
released by Emerging Infectious Diseases, a C.D.C. publication, the
Zika virus was shown to be still replicating in the brains of infants
days or even weeks after they were born. It was also shown to persist in
placentas for up to seven months.
For
that study, C.D.C. scientists analyzed autopsy brain tissue from eight
infants who were born alive but died later — sometimes within a few
hours, in one case after two months.
The
virus persisted “much longer than we expected,” said Julu Bhatnagar,
the head of molecular pathology for the C.D.C.’s infectious diseases
pathology branch and the study’s lead author.
The
virus was also found in the placentas of mothers whose babies appeared
healthy at birth and came up negative on both types of Zika test.
That suggests that all infants whose mothers have had Zika should be monitored after birth, Dr. Ko said.
Dr.
Ernesto T. A. Marques Jr., an infectious disease specialist at the
University of Pittsburgh and the Oswaldo Cruz Foundation in Brazil, said
that study was consistent with what he had seen in Recife, Brazil. Some
of the 370 children being followed there appeared to be still infected
with Zika and were still being damaged by it even a year after birth.
Some
of the babies were suffering seizures, and some had to be fed through
nasogastric tubes because they could not swallow and their intestines
could barely move food along, he said. Doctors there hoped to find some
sort of antiviral drug that could kill the virus in those children, he
added.
Another recent study
found that some babies born small-headed but not microcephalic went on
to meet the definition of microcephaly later because their heads stopped
growing after birth, suggesting that damage was continuing.
Current guidelines recommend that pregnant women are given at least two ultrasound scans, at 8 to 14 weeks and then between 18 and 21 weeks to check for abnormalities, including brain defects.
But the researchers were concerned that the diagnostic accuracy of ultrasound scans is limited; estimated at around 70%. This could lead to some women terminating their pregnancy due to thinking they will have a miscarriage or stillbirth, when in fact the pregnancy was healthy.
So, researchers wanted to see if using an additional MRI scan when a brain defect was suspected would lead to an improvement in diagnosis rates.
They considered 570 cases and found a 25% improvement in diagnosis rates when an MRI scan was used in addition to the ultrasound scan. They also found that almost all women included in the study thought it was a good idea.
The researchers propose that any pregnant woman whose ultrasound scan suggests her baby may have a brain defect should have an MRI scan as well for a more accurate diagnosis.
Where did the story come from?
This UK based study was carried out by researchers from The University of Sheffield, the University of Newcastle, the University of Birmingham, Birmingham Women's Foundation Trust, and Leeds Teaching Hospitals NHS Trust and was funded by the National Institute for Health Research Health Technology Assessment Programme.The study was published in the peer-reviewed medical journal The Lancet and is open-access, meaning it is free to read online.
BBC News' reporting of the story was accurate, making the point that the extra test is most useful in borderline cases when doctors are uncertain of the outcome.
What kind of research was this?
This was a large multi-centre prospective cohort study in the UK, including 16 foetal medicine centres.The study included 570 cases of potential foetal brain abnormality that were detected by ultrasound.
The cases were then assessed to see if in-utero MRI (iuMRI) scans (scans used during pregnancy) when used in addition to ultrasound improved diagnostic accuracy.
Prospective cohort studies are useful for assessing diagnostic accuracy as the results of any testing can then be compared against the actual outcome.
What did the research involve?
Researchers recruited women aged 16 or over between 2011 and 2014. In total, 570 cases were included whose unborn baby had a foetal brain abnormality detected by ultrasound.Cases were divided into two groups depending when in pregnancy the initial ultrasound scan took place:
- between 18 and 24 weeks (n=369)
- at or after 24 weeks (n=201)
After the ultrasound scan, doctors were asked to record their certainty of diagnosis for each brain abnormality from very unsure (10% certain) to highly confident (90% certain).
Less than 14 days afterwards, participants had an iuMRI scan at one of six sites across the UK.
The radiologist was aware of the level of certainty recorded by the ultrasound expert before the iuMRI was done. The radiologist was then required to comment on the diagnosis made with the ultrasound and add extra diagnoses where appropriate.
Diagnostic accuracy was assessed separately for the group who had the initial ultrasound scan between 18 and 24 weeks and the group who had it at 24 weeks or later.
This was done either by using brain scans for babies who were delivered during a viable pregnancy or by autopsy or post-mortem MRI in cases of termination of pregnancy, stillbirth or neonatal death.
What were the basic results?
When using the iuMRI scan in addition to the standard ultrasound, diagnostic accuracy was improved by:- 23% (95% confidence interval (CI) = 18 to 27) in the 18 weeks to less than 24 weeks group
- 29% (95% CI 23 to 36) in the 24 weeks and older group
Diagnoses were reported with high confidence on ultrasound in 465 of 570 cases compared with 544 of 570 cases when combined with iuMRI.
The MRI scans provided additional diagnostic information in 49% of cases, changed prognostic information (information regarding outcomes) in at least 20% of cases and led to changes in clinical management in more than one in three cases.
At least 95% of women who took part in the study said they would have an iuMRI scan if a future pregnancy was also complicated by a foetal brain abnormality.
How did the researchers interpret the results?
The researchers conclude that "our results indicate a 23% absolute increase in diagnostic accuracy when iuMRI is used to supplement ultrasound imaging in the 18 weeks to younger than 24 weeks gestational age group of fetuses and a 29% increase in the 24 weeks or older fetuses."Diagnostic confidence is also improved when iuMRI is used to assess prenatal fetal neuropathology as an adjunct to ultrasound."
They add that "the increased diagnostic accuracy and confidence results in changes in counselling and clinical management in a high proportion of cases. These factors, in conjunction with high patient acceptability, lead us to propose that any fetus with a suspected brain abnormality on ultrasound should have iuMRI before definitive counselling."
Conclusion
Overall, the study provides evidence for a link between having an iuMRI when a brain abnormality has been detected in the foetus and improved diagnostic accuracy. This improvement led to a change in management in a significant minority of cases.This study provides strong evidence for adding this extra scan in cases when brain abnormalities are detected. Also, most women involved in the study thought this extra scan was a good idea if brain abnormalities were detected in the ultrasound scan.
However, there are some minor limitations to this pragmatic study which are acknowledged by the researchers:
- The radiologists assessing the iuMRI scans had already seen the notes from the ultrasound, which may have led to confirmation bias, where they are more likely to agree with the opinion already put forward.
- The iuMRI scan was carried out up to 14 days after the ultrasound. The time difference between examinations is an important factor for diagnostic accuracy as the foetal brain is growing and maturing rapidly. Most brain abnormalities will be easier to detect in more mature foetal brains. This makes it difficult to directly compare the accuracy of diagnosis from the ultrasound with that of the iuMRI scan. At this later stage, ultrasound scans may have also been more accurate.
- The majority of cases were taken from one site and the demographic of women in this area may differ compared to other areas and therefore results may not apply to other areas in the UK.
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