Pathfinder
Editor, Senior Moderator
DISCLAIMER
This paper was submitted to the Bulletin of the World Health Organization on 29 January 2016
and was posted to the Zika open site on 4 February 2016, according to the protocol for public
health emergencies for international concern as described in Christopher Dye et al.
(http://dx.doi.org/10.2471/BLT.16.170860).
The information herein is available for unrestricted use, distribution and reproduction in any
medium, provided that the original work is properly cited as indicated by the Creative
Commons Attribution 3.0 Intergovernmental Organizations licence (CC BY IGO 3.0).
RECOMMENDED CITATION
Soares de Ara?jo JS, Regis CT, Gomes RGS, Tavares TR, Rocha dos Santos C, Assun??o PM, et al.
Microcephaly in northeast Brazil: a review of 16 208 births between 2012 and 2015.
[Submitted] Bull World Health Organ, E-pub: 4 Feb 2016. doi:
http://dx.doi.org/10.2471/BLT.16.170639
Microcephaly in northeastern Brazil: a review of 16 208 births between 2012 and 2015
Juliana Sousa Soares de Ara?jo,a
Cl?udio Teixeira Regis,a
Renata Grig?rio Silva
Gomes,a
Thiago Ribeiro Tavares,a
C?cera Rocha dos Santos,a
Patr?cia Melo
Assun??o,b
Renata Val?ria N?brega,b
Diana de F?tima Alves Pinto,b
Bruno Vin?cius
Dantas Bezerrab
& Sandra da Silva Mattosa
a
C?rculo do Cora??o de Pernambuco, Sandra da Silva Mattos. Av. Agamenon Magalh?es
2760, Paissandu, Recife ? Pernambuco - CEP 52010-902, Brazil.
b
Secretaria de Sa?de do Estado da Para?ba, Jo?o Pessoa, Brazil.
Correspondence to Sandra da Silva Mattos (email: ssmattos@cardiol.br).
(Submitted: 29 January 2016)
Abstract:
A recent outbreak of microcephaly has been reported from Northeast Brazil. Neither its
aetiology, nor its clinical significance has yet been fully established. A complication from an
intrauterine infection with the Zika virus (ZIKV) is, thus far, the most explored hypothesis. In
Para?ba, one of the nine States within the epicentre of the epidemic, 21 medical centres
collaborate, via telemedicine since 2012, in a paediatric cardiology network. The Network?s
database currently stores information on more than 100,000 neonates. To support the
microcephaly research, from December 1st to 31st, 2015, the Network ran a task force and
rescued the head circumference from 16,208 neonates. A much higher than expected
incidence of microcephaly was observed, varying from 2% to 8% according to the utilized
classification criteria. These findings raise questions about the condition?s diagnosis and its
notification. An observed presentation?s seasonality might reflect that of infections carried on
by the Aedis aegypti vector. However, the temporal fluctuation was documented since late
2012, before the allegedly entry of the ZIKV in Brazil, in mid-2014. Further questions are raised
on both the epidemiological surveillance of the Aedis aegypti infections, as well as on different
aetiological possibilities for the outbreak. At this stage, follow-up studies in the children
diagnosed with microcephaly are mandatory prior to concluding what problem we are facing;
how it came about and which consequences it may, or not, bring to the Brazilian population in
years to come.
Introduction
Microcephaly is a clinical finding and not a disease. It is defined as an occipital-frontal head
circumference (OFC) smaller than expected for gestational age and gender. It is reported to
occur in one in every 6,250 to 8,500 live births(1). Since the growth of the cranium depends on
the forces of an expanding brain, microcephaly is an indicator of an undersized brain. Whilst
the measurement of OFC is a trusted assessment of intracranial brain volume, controversy
exists about the lower limit for this measurement as well as for the need of ethnically
controlled data(2). Furthermore, the clinical implications of an undersized brain are far more
complex to establish.
From November 2015, there has been a dramatic increase in reported numbers of
microcephaly in Northeast Brazil. The public health implications could be enormous. Whilst
clinical and epidemiological studies are necessary to establish the extent of the problem, there
is an understandable pressure from the Brazilian population, particularly women at
reproductive age, for quick answers.
The total number of cases reported with microcephaly in this period, from 20 Brazilian States,
approached 3,000(3). Over 85% of them are from the Northeast. Para?ba, one of the nine States
from this Region, is second in number of reported cases. It has 21,847 mi?, and a population of
3,944 millions and has reported on nearly 500 cases and first documented the presence of
ZIKV in amniotic fluid from two microcephalic foetuses(4)
.
Also, since 2012, in collaboration with the NGO ? C?rculo do Cora??o, Para?ba runs a Paediatric
Cardiology and Network(5), which among other actions, has screened and stores cardiovascular
data from over 100,000 neonates.
Head circumference was not included in the original data set. However, due to the pressing
needs to shed light on the microcephaly crisis, the Network proposed a four-week task force to
rescue this information in 10% of the dataset. This report summarizes the results from the task
force.
Methodology
This is a descriptive, observational and transverse study, with data from the C?rculo do Cora??o
- Paediatric Cardiology and Perinatology Network (RCP-CirCor) Database from Para?ba, in
Northeast Brazil.
Sample collection
Lists with ID number, mother?s name and date of birth of all RCP-CirCor neonates were sent to
each participant site. Nurses were advised to collect OFC and thorax circumference
information from delivery room books or patient?s files in 10% of patients and to spread the
search over the four-year period, to reflect the problem over time. Remaining information was
retrieved from the Network?s database and included mother?s name and address, gestational
age, gender, weight and height at birth. No funding was allocated to this task force.
Microcephaly criteria utilized
In this study, classification of microcephaly was based on three different criteria, as follows:
1. Brazilian Health Ministry proposed criteria, where microcephaly equals an OFC smaller
than 32 cm for term neonates.(6)
2. Fenton curves, where microcephaly equals an OFC less than -3 standard deviation (SD)
for age and gender.(7)
3. Proportionality criteria, where microcephaly equals an OFC less than ((height/2) + 10) ?
2.(8)
Microcephaly classification
Neonates were classified with microcephaly according to each one of the three criteria. A
separate group was created for those who fulfilled all three criteria. Finally, those who fell into
the lower third in each criterion were grouped as extreme cases of microcephaly.
Statistical analysis
The software R were used for data analysis, which included Friedman as the statistical model
for hypothesis determination with the confidence interval of 95%.
Results
Between Dec 1st and 31st 2015, OFC was collected from 16,208 neonates, born between
January 1st 2012 and December 31st 2015, in 21 different public health centres from Para?ba.
There was an even distribution of gender, most of them were term babies, weighting over
3,000g and measuring over 45cm at birth. Table 1 describes the population.
Microcephaly classification
Depending on the criteria utilized, in this sample, from 4% to 8% of kids born between 2012
and 2015 had microcephaly. Neonates fulfilling all three criteria accounted for nearly 2% of the
sample. If, however, only the extreme cases are considered, the neonates fulfilling all three
criteria fall within the expected ranges reported for microcephaly worldwide. Table 2
summarizes these findings.
Temporal distribution
The distribution of cases of microcephaly between 2012 and 2015 is observed in Fig. 1. A
temporal oscillation is observed which is concordant in all three criteria. The numbers are
greater than expected since the end of 2012 and with its sharpest peak in mid-2014. However
when only the extreme cases of microcephaly are considered a significant (p=0.001) increase
in numbers is observed in recent months as shown on Figure 2.
Discussion
In 2000, SINASC (Brazilian Live Birth Information System) reported that the prevalence of
microcephaly in Brazilian newborns was 5.5 cases/ 100,000 live births and in 2010 it was 5.7
cases / 100,000 live births(7). Over the last three monts it went up to 99.7 per 100.000 live
births which corresponds to a twentyfold increase(3)
.
In this study, independent of the classification criteria used, we demonstrated a much higher
incidence of microcephaly between 2012 and 2015.
Projecting our findings to the total number of live births in Para?ba, in 2014 (n=58,147), the
number of neonates born with microcephaly in that year would have been 4,652 by the Health
Ministry proposed criteria, 2,442 by the Fenton curves and 2,907 by the proportionality
criteria. Neonates classified with microcephaly by all three criteria would have been 1,105.
These observations highlight the need to review the situation carefully. Many questions need
to be answered prior to concluding what problem we are facing, how it came about and which
consequences it is likely to bring to the Brazilian population in years to come.
The first question to be addressed is the real incidence of microcephaly in Northeast Brazil.
The discrepancy from the expected and found cases may reflect the condition?s major subnotification
in the official sites in recent years coupled with an even greater epidemiological
crisis than presumed or simple the need to revise the diagnostic criteria for the condition.
The numbers of very extreme cases of microcephaly, for instance, while significantly increasing
over the last few months, are much smaller and until recently fell within the expected ranges
for the worldwide reported incidence.
It is possible that a high incidence of milder forms microcephaly has been occurring well before
the current outbreak, but that only those extreme cases, with classical phenotypes, were being
notified.
And as the number of extreme cases increased over these past three or four months so did the
awareness of health professionals who started to notify milder forms.
What remains to be determined is the clinical significance of these milder forms, which
account for the vast majority of the reported cases. Could a 31cm or 32cm OFC in a term
neonate, for instance, be within normal limits for this particular population? Could ethnical or
nutritional components explain these findings? Are we facing large numbers of a neurological
disease or observing an anthropometric variation of normality?
The microcephaly occurrence displays a temporal distribution. Infections caused by the Aedes
aegypti, a proposed aetiology for the outbreak, also demonstrate temporal fluctuations.(9)
Currently, the association with the ZIKV infection is the most explored possibility. Evidence of
perinatal transmission of ZIKV(10) together with its strong neurotropism(11) and its
documentation in amniotic fluid of foetuses with microcephaly(4) are factors that favour this
hypothesis. However, if the ZIKV were indeed introduced in Brazil at the World Cup in mid
2014(12), the outbreak of microcephaly would have preceded it. ZIKV has been identified in
Africa over 50 years ago, and neither there nor in the outbreaks outside Africa, such an
association with microcephaly has been reported(13). However, recently ZIKV has been
associated to a number of conditions including Guillain-Barr? syndrome during a recent
outbreak of the infection in the French Polynesia(10)
.
Many other potential factors need to be considered as the cause of the outbreak. Among them
figures the possibility of boosting effects from associated infections, perhaps even viral
infections, such as DENV and CHIKV, both carried by the same Aedes aegypti vector. Also to be
considered is teratogens exposure, such as vaccines or drugs used in early pregnancy.(1,2)
Further, malnutrition, which has previously been associated to microcephaly, could have an
intensifying effect when coupled with other aetiological factors. Indeed, most of the reported
cases have occurred in low-income families.
Thus far, controlling the Aedes aegypti vector has been a major public health strategy, which is
justified not only by its potential benefits in holding back the epidemic, which may or may not
hold true, but for its numerous other benefits to the population.
We can only conclude that we are facing a new and challenging public health problem and that
limited epidemiological and clinical data hinders conclusions at this early stage.
Further retrospective studies, as well as follow-up investigations on both the clear-cut
microcephaly as well as the borderline or ?smaller head? neonate are paramount to clarify the
aetiology as well as the neurological consequences of these findings and prompt management
strategies to the affected populations.
Acknowledgements
The RCP-CirCor wishes to acknowledge all its members, particularly the nursed in charge of the
various maternity centres for the speedy job and data collection and storage during the month
of December.
More...
http://www.who.int/bulletin/online_first/16-170639.pdf?ua=1
http://www.who.int/bulletin/online_first/zika_open/en/
This paper was submitted to the Bulletin of the World Health Organization on 29 January 2016
and was posted to the Zika open site on 4 February 2016, according to the protocol for public
health emergencies for international concern as described in Christopher Dye et al.
(http://dx.doi.org/10.2471/BLT.16.170860).
The information herein is available for unrestricted use, distribution and reproduction in any
medium, provided that the original work is properly cited as indicated by the Creative
Commons Attribution 3.0 Intergovernmental Organizations licence (CC BY IGO 3.0).
RECOMMENDED CITATION
Soares de Ara?jo JS, Regis CT, Gomes RGS, Tavares TR, Rocha dos Santos C, Assun??o PM, et al.
Microcephaly in northeast Brazil: a review of 16 208 births between 2012 and 2015.
[Submitted] Bull World Health Organ, E-pub: 4 Feb 2016. doi:
http://dx.doi.org/10.2471/BLT.16.170639
Microcephaly in northeastern Brazil: a review of 16 208 births between 2012 and 2015
Juliana Sousa Soares de Ara?jo,a
Cl?udio Teixeira Regis,a
Renata Grig?rio Silva
Gomes,a
Thiago Ribeiro Tavares,a
C?cera Rocha dos Santos,a
Patr?cia Melo
Assun??o,b
Renata Val?ria N?brega,b
Diana de F?tima Alves Pinto,b
Bruno Vin?cius
Dantas Bezerrab
& Sandra da Silva Mattosa
a
C?rculo do Cora??o de Pernambuco, Sandra da Silva Mattos. Av. Agamenon Magalh?es
2760, Paissandu, Recife ? Pernambuco - CEP 52010-902, Brazil.
b
Secretaria de Sa?de do Estado da Para?ba, Jo?o Pessoa, Brazil.
Correspondence to Sandra da Silva Mattos (email: ssmattos@cardiol.br).
(Submitted: 29 January 2016)
Abstract:
A recent outbreak of microcephaly has been reported from Northeast Brazil. Neither its
aetiology, nor its clinical significance has yet been fully established. A complication from an
intrauterine infection with the Zika virus (ZIKV) is, thus far, the most explored hypothesis. In
Para?ba, one of the nine States within the epicentre of the epidemic, 21 medical centres
collaborate, via telemedicine since 2012, in a paediatric cardiology network. The Network?s
database currently stores information on more than 100,000 neonates. To support the
microcephaly research, from December 1st to 31st, 2015, the Network ran a task force and
rescued the head circumference from 16,208 neonates. A much higher than expected
incidence of microcephaly was observed, varying from 2% to 8% according to the utilized
classification criteria. These findings raise questions about the condition?s diagnosis and its
notification. An observed presentation?s seasonality might reflect that of infections carried on
by the Aedis aegypti vector. However, the temporal fluctuation was documented since late
2012, before the allegedly entry of the ZIKV in Brazil, in mid-2014. Further questions are raised
on both the epidemiological surveillance of the Aedis aegypti infections, as well as on different
aetiological possibilities for the outbreak. At this stage, follow-up studies in the children
diagnosed with microcephaly are mandatory prior to concluding what problem we are facing;
how it came about and which consequences it may, or not, bring to the Brazilian population in
years to come.
Introduction
Microcephaly is a clinical finding and not a disease. It is defined as an occipital-frontal head
circumference (OFC) smaller than expected for gestational age and gender. It is reported to
occur in one in every 6,250 to 8,500 live births(1). Since the growth of the cranium depends on
the forces of an expanding brain, microcephaly is an indicator of an undersized brain. Whilst
the measurement of OFC is a trusted assessment of intracranial brain volume, controversy
exists about the lower limit for this measurement as well as for the need of ethnically
controlled data(2). Furthermore, the clinical implications of an undersized brain are far more
complex to establish.
From November 2015, there has been a dramatic increase in reported numbers of
microcephaly in Northeast Brazil. The public health implications could be enormous. Whilst
clinical and epidemiological studies are necessary to establish the extent of the problem, there
is an understandable pressure from the Brazilian population, particularly women at
reproductive age, for quick answers.
The total number of cases reported with microcephaly in this period, from 20 Brazilian States,
approached 3,000(3). Over 85% of them are from the Northeast. Para?ba, one of the nine States
from this Region, is second in number of reported cases. It has 21,847 mi?, and a population of
3,944 millions and has reported on nearly 500 cases and first documented the presence of
ZIKV in amniotic fluid from two microcephalic foetuses(4)
.
Also, since 2012, in collaboration with the NGO ? C?rculo do Cora??o, Para?ba runs a Paediatric
Cardiology and Network(5), which among other actions, has screened and stores cardiovascular
data from over 100,000 neonates.
Head circumference was not included in the original data set. However, due to the pressing
needs to shed light on the microcephaly crisis, the Network proposed a four-week task force to
rescue this information in 10% of the dataset. This report summarizes the results from the task
force.
Methodology
This is a descriptive, observational and transverse study, with data from the C?rculo do Cora??o
- Paediatric Cardiology and Perinatology Network (RCP-CirCor) Database from Para?ba, in
Northeast Brazil.
Sample collection
Lists with ID number, mother?s name and date of birth of all RCP-CirCor neonates were sent to
each participant site. Nurses were advised to collect OFC and thorax circumference
information from delivery room books or patient?s files in 10% of patients and to spread the
search over the four-year period, to reflect the problem over time. Remaining information was
retrieved from the Network?s database and included mother?s name and address, gestational
age, gender, weight and height at birth. No funding was allocated to this task force.
Microcephaly criteria utilized
In this study, classification of microcephaly was based on three different criteria, as follows:
1. Brazilian Health Ministry proposed criteria, where microcephaly equals an OFC smaller
than 32 cm for term neonates.(6)
2. Fenton curves, where microcephaly equals an OFC less than -3 standard deviation (SD)
for age and gender.(7)
3. Proportionality criteria, where microcephaly equals an OFC less than ((height/2) + 10) ?
2.(8)
Microcephaly classification
Neonates were classified with microcephaly according to each one of the three criteria. A
separate group was created for those who fulfilled all three criteria. Finally, those who fell into
the lower third in each criterion were grouped as extreme cases of microcephaly.
Statistical analysis
The software R were used for data analysis, which included Friedman as the statistical model
for hypothesis determination with the confidence interval of 95%.
Results
Between Dec 1st and 31st 2015, OFC was collected from 16,208 neonates, born between
January 1st 2012 and December 31st 2015, in 21 different public health centres from Para?ba.
There was an even distribution of gender, most of them were term babies, weighting over
3,000g and measuring over 45cm at birth. Table 1 describes the population.
Microcephaly classification
Depending on the criteria utilized, in this sample, from 4% to 8% of kids born between 2012
and 2015 had microcephaly. Neonates fulfilling all three criteria accounted for nearly 2% of the
sample. If, however, only the extreme cases are considered, the neonates fulfilling all three
criteria fall within the expected ranges reported for microcephaly worldwide. Table 2
summarizes these findings.
Temporal distribution
The distribution of cases of microcephaly between 2012 and 2015 is observed in Fig. 1. A
temporal oscillation is observed which is concordant in all three criteria. The numbers are
greater than expected since the end of 2012 and with its sharpest peak in mid-2014. However
when only the extreme cases of microcephaly are considered a significant (p=0.001) increase
in numbers is observed in recent months as shown on Figure 2.
Discussion
In 2000, SINASC (Brazilian Live Birth Information System) reported that the prevalence of
microcephaly in Brazilian newborns was 5.5 cases/ 100,000 live births and in 2010 it was 5.7
cases / 100,000 live births(7). Over the last three monts it went up to 99.7 per 100.000 live
births which corresponds to a twentyfold increase(3)
.
In this study, independent of the classification criteria used, we demonstrated a much higher
incidence of microcephaly between 2012 and 2015.
Projecting our findings to the total number of live births in Para?ba, in 2014 (n=58,147), the
number of neonates born with microcephaly in that year would have been 4,652 by the Health
Ministry proposed criteria, 2,442 by the Fenton curves and 2,907 by the proportionality
criteria. Neonates classified with microcephaly by all three criteria would have been 1,105.
These observations highlight the need to review the situation carefully. Many questions need
to be answered prior to concluding what problem we are facing, how it came about and which
consequences it is likely to bring to the Brazilian population in years to come.
The first question to be addressed is the real incidence of microcephaly in Northeast Brazil.
The discrepancy from the expected and found cases may reflect the condition?s major subnotification
in the official sites in recent years coupled with an even greater epidemiological
crisis than presumed or simple the need to revise the diagnostic criteria for the condition.
The numbers of very extreme cases of microcephaly, for instance, while significantly increasing
over the last few months, are much smaller and until recently fell within the expected ranges
for the worldwide reported incidence.
It is possible that a high incidence of milder forms microcephaly has been occurring well before
the current outbreak, but that only those extreme cases, with classical phenotypes, were being
notified.
And as the number of extreme cases increased over these past three or four months so did the
awareness of health professionals who started to notify milder forms.
What remains to be determined is the clinical significance of these milder forms, which
account for the vast majority of the reported cases. Could a 31cm or 32cm OFC in a term
neonate, for instance, be within normal limits for this particular population? Could ethnical or
nutritional components explain these findings? Are we facing large numbers of a neurological
disease or observing an anthropometric variation of normality?
The microcephaly occurrence displays a temporal distribution. Infections caused by the Aedes
aegypti, a proposed aetiology for the outbreak, also demonstrate temporal fluctuations.(9)
Currently, the association with the ZIKV infection is the most explored possibility. Evidence of
perinatal transmission of ZIKV(10) together with its strong neurotropism(11) and its
documentation in amniotic fluid of foetuses with microcephaly(4) are factors that favour this
hypothesis. However, if the ZIKV were indeed introduced in Brazil at the World Cup in mid
2014(12), the outbreak of microcephaly would have preceded it. ZIKV has been identified in
Africa over 50 years ago, and neither there nor in the outbreaks outside Africa, such an
association with microcephaly has been reported(13). However, recently ZIKV has been
associated to a number of conditions including Guillain-Barr? syndrome during a recent
outbreak of the infection in the French Polynesia(10)
.
Many other potential factors need to be considered as the cause of the outbreak. Among them
figures the possibility of boosting effects from associated infections, perhaps even viral
infections, such as DENV and CHIKV, both carried by the same Aedes aegypti vector. Also to be
considered is teratogens exposure, such as vaccines or drugs used in early pregnancy.(1,2)
Further, malnutrition, which has previously been associated to microcephaly, could have an
intensifying effect when coupled with other aetiological factors. Indeed, most of the reported
cases have occurred in low-income families.
Thus far, controlling the Aedes aegypti vector has been a major public health strategy, which is
justified not only by its potential benefits in holding back the epidemic, which may or may not
hold true, but for its numerous other benefits to the population.
We can only conclude that we are facing a new and challenging public health problem and that
limited epidemiological and clinical data hinders conclusions at this early stage.
Further retrospective studies, as well as follow-up investigations on both the clear-cut
microcephaly as well as the borderline or ?smaller head? neonate are paramount to clarify the
aetiology as well as the neurological consequences of these findings and prompt management
strategies to the affected populations.
Acknowledgements
The RCP-CirCor wishes to acknowledge all its members, particularly the nursed in charge of the
various maternity centres for the speedy job and data collection and storage during the month
of December.
More...
http://www.who.int/bulletin/online_first/16-170639.pdf?ua=1
http://www.who.int/bulletin/online_first/zika_open/en/