Publication: Bulletin of the World Health Organization; Type: Research in emergencies

Article ID: BLT.16.171215

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RECOMMENDED CITATION

Rocha HAL, Correia LL, Leite AJM, Campos JS, Cavalcante e Silva A, Machado MMT,
Rocha SGMO, Saraiva de Almeida NMG, Alves da Cunha AJL. Microcephaly: normality
parameters and its determinants in northeastern Brazil: a multicentre prospective cohort study
[Submitted]. Bull World Health Organ E-pub: 8 Feb 2016. doi:
http://dx.doi.org/10.2471/BLT.16.171215

Microcephaly: normality parameters and its determinants

in northeastern Brazil: a multicentre prospective cohort
study
Hermano Alexandre Lima Rocha,a Luciano Lima Correia,a lvaro Jorge
Madeiro Leite,a Jocileide Sales Campos,b Anamaria Cavalcante e Silva,b
Mrcia Maria Tavares Machado,a Sabrina Gabriele Maia Oliveira
Rocha,a Ndia Maria Giro Saraiva de Almeidaa & Antonio Jos Ledo
Alves da Cunhac
a
Federal University of Cear, Rua Prof. Costa Mendes 1608, Fortaleza,CE 60430140, Brazil.
b
Unichristus, Fortaleza, Brazil.
c
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Correspondence to Hermano Alexandre Lima Rocha (email: [email protected]).
(Submitted: 7 February 2016 Published online: 8 February 2016)

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 Publication: Bulletin of the World Health Organization; Type: Research in emergencies
Article ID: BLT.16.171215
Abstract

Brazil was marked by a serious epidemic of microcephaly due to still obscure causes.
According to the Ministry of Health, the number of suspected cases of microcephaly reached
2401. However, there is controversy in Brazil regarding the most appropriate cut-off point
and diagnosis criteria. The present study aimed to measure the prevalence of microcephaly
and identify its determinants, in a prospective cohort from a multicentre hospital-based study.
The sample comprised 3623 live births admitted to the NICU, the dependent variable being
cephalic perimeter. Bootstrap and logistic regression models were used to analyse data. 32 cm
corresponded to tenth percentile in this population, with a confidence interval between 31.82
and 32.18. Intrauterine growth restriction, pregnancies resulting in congenital anomalies,
oligohydramnios and the maternal use of steroids were associated with microcephaly. This
work raises discussion on the cut-off point used for the diagnosis of microcephaly at a
population level in a country with an outbreak as well as factors that can be associated with
the outcome presented.

Introduction
The year 2015 in Brazil was marked by a serious epidemic of microcephaly due to still
obscure causes. According to the Ministry of Health of Brazil, the number of suspected cases
of microcephaly reached 2401 in 19 states and the Federal District, with 29 cases evolving to
death. The states with the highest number of cases were in the Northeast region of Brazil,
including all of its nine states (1).
The initial diagnosis of microcephaly is performed in the maternity ward by measuring
the cephalic perimeter at birth. However, there is controversy in Brazil regarding the most
appropriate cut-off point (2, 3). After the identification of an excessive number of suspected
cases, the Ministry of Health of Brazil issued a statement reducing the cephalic perimeter
representative of the suspicion of microcephaly from 33 cm to 32 cm (4).
The volumes of three main components (brain matter, cerebrospinal fluid and blood)
determine the size of the skull during childhood. Microcephaly is defined as an occipitofrontal
circumference measurement of less than the third percentile or below two standard deviations
of the mean measurement for age, gender and ethnicity (5).
Microcephaly can be primary when the brain is small because it does not undergo
proper embryonic development due to genetic factors and malformations. Microcephaly can
also be secondary, when the brain completes normal embryonic development but suffers
damage that alters its further development, including damage caused by vascular processes,
perinatal diseases and antenatal systemic postnatal diseases. A study in Germany found that
41% of children diagnosed with microcephaly did not have a definitive diagnosis (3).
Approximately 90% of microcephaly cases are associated with mental retardation,
except in those with familiar origin, which may exhibit normal cognitive development. The
type and the severity level of sequelae may vary in each case. Treatment in the early years of
life enhance development and the quality of life (6). The later recovery of the cephalic
perimeter can guarantee normal cognitive development (7).
The pathogenesis of microcephaly is heterogeneous, ranging from genetic causes and
intrauterine growth restriction to environmental factors, which can influence the development
and size of the brain (6, 8). Studies found an association between microcephaly and diarrhoea
and malnutrition (9). Infections during pregnancy can also cause microcephaly, including
cytomegalovirus (10), toxoplasmosis (11) and rubella virus infection (12, 13).
In Brazil, the recent outbreak of zika virus infection and the observed increase of cases
of microcephaly has led to epidemiological investigation of the possible association of this
virus with the malformation. A study carried out in French Polynesia identified probable zika
virus transmission during childbirth to the new-born and a case of microcephaly among the
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 Publication: Bulletin of the World Health Organization; Type: Research in emergencies
Article ID: BLT.16.171215
two cases evaluated; however, this case also suffered from intrauterine growth restriction
(14).
The present study aimed to measure the prevalence of microcephaly and identify its
determinants in the nine states in the Northeast region of Brazil, which presents the highest
number of cases in the country, using data relating to a period prior to the current outbreak.
We intend to contribute to the scientific discussion of the problem by providing baseline
information of relevance.

Methods
Study Design
This study utilized a prospective cohort from a multicentre hospital-based study of live
births at gestational age from 230/7 weeks, carried out by RENOSPE (Perinatal Health
Network of Northeast, Brazil). The purpose of this network was to enhance the competence of
the public health system in areas such as management, assistance, education and perinatal
research through the articulation of a network of neonatal units from public secondary and
tertiary maternity wards located in states in the north and north-east of Brazil (15).

Setting
The study was conducted in high-risk neonatal units of public maternity wards located in
capitals of nine north-eastern states, namely Maranho, Piau, Cear, Rio Grande do Norte,
Paraba, Pernambuco, Alagoas, Sergipe and Bahia. Together, the north-eastern region
comprises a population of 53 million people, most of it living in a semiarid climate.
During the period from July to December 2007, 37 health establishments participated in
the study: 4 (10.8%) in Maranho, 2 (5.4%) in Piau, 7 (18.9%) in Cear, 3 (8.2%) in Rio
Grande do Norte, 7 (18.9%) in Paraba, 6 (16.2%) in Pernambuco, 2 (5.4%) in Alagoas, 2
(5.4%) in Sergipe and 4 (10.8%) in Bahia.
The collection of the data in each unit was carried out prospectively from the time of
admission to the time of discharge or death by a field researcher (doctor or nurse) trained by a
RENOSPE coordinator.

Participants
The study sample included new-borns hospitalized after birth in the Neonatal Intensive
Care Unit (NICU) whose record in the original database contained the discharge from the
NICU and entrance to the NICU that did not include transfer from another health facility.
Exclusion criteria were infants admitted to the NICU with a transfer, congenital
malformations and death that occurred in the delivery room. Children with a lack of
information on these fields were also excluded.

Study Size
The sample comprised 3623 live births admitted to the NICU members of RENOSPE. Of
these, 654 (18.1%) evolved to death during the neonatal period (at the NICU due to death)
and 2969 (81.9%) who survived were admitted to the intensive care unit. Only the new-born
infants with a gestational time between 37 and 41 weeks were included in the analysis,
yielding 1314 individuals. This sample size conferred a power of approximately 80% for a
type I error of 0.05 to identify risk differences as small as 2 with an estimated prevalence of
5% (exact number necessary for this power is 1418).

Variables
The dependent variable was cephalic perimeter, which was expressed as a continuous
variable and was also categorized into positive or negative for microcephaly according to the
definition provided by OMS growth chart curves (3).
The independent variables were classified as follows:
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 Publication: Bulletin of the World Health Organization; Type: Research in emergencies
Article ID: BLT.16.171215

Block I (distal variables): social, economic and demographic characteristics:

Race, mothers years of study, mothers occupation.
Block II (intermediate variables): maternal characteristics:
Maternal age (in years), number of pregnancies (including current), number of
abortions, number of stillborn children.
Block II (proximal variables): prenatal care and childbirth:
Number of prenatal visits, type of birth, length of pregnancy in weeks, use of antenatal
corticosteroids (among new-borns with birth weight less than 1,500 g), complications in
pregnancy (urinary infection, chorioamnionitis, acute foetal distress, premature rupture
of the membranes, intrauterine growth retardation, premature labour, premature
separation of placenta, hypertension, preeclampsia, eclampsia, oligohydramnios,
gestational diabetes, previous diabetes, positive HBsAg antigen, HIV/hepatitis B,
syphilis, toxoplasmosis).

Statistical methods
The public domain software EPI INFO 6.04 D was used for data file creation and
processing.
The general description of the sample was presented using counts and percentages for
categorical variables and measures of central tendency for numeric variables. The normality
of the distribution of numeric variables was tested with the Kolmogorov-Smirnov test.
Central tendency analyses were performed to identify normal population and percentile
values with the bootstrap technique using 1000 samples for each analysis. Descriptive box
plots were built with subgroups. To identify statistical associations, regressive logistic
bivariate models were used. Variables identified with p-values less than 0.1 were considered
for the construction of a hierarchical regressive logistic multivariate model. The gross risk
rates adjusted with their respective 95% confidence intervals were tabulated and analysed.
Analyses were performed with SPSS for Windows software, v 17 (SPSS Inc.).

Ethical statements
The references of bioethics, recommended in resolution 196/96 of the National Health
Council (CNS), were considered in this study. The project was submitted and approved by the
Research Ethics Committee of the Federal University of Cear under Protocol 31/2007.

Results

A total of 1006 children participated in this analysis, geographically distributed as

follows: the State of Maranho (295), State of Cear (257), State of Bahia (181), State of
Alagoas (139), State of Paraba (134), State of Sergipe (79), State of Piaui (60), and the State
of Rio Grande do Norte (44). The State of Pernambuco did not contribute to the sample due to
the absence of data collection in this state by the field researchers.
The following results present a descriptive analysis of the normal patterns of the
cephalic perimeter of children, followed by multivariate analysis of risk factors associated
with microcephaly in this population.
The average cephalic perimeter of this population of children in north-eastern Brazil
was 34.29 cm, with a standard deviation of 2.50 cm.
Graph 1. Cephalic perimeter measured at birth in states of the northeast region of Brazil,
2007.

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Article ID: BLT.16.171215

Graph 1 shows that extreme values were found more frequently in the states that
contributed more cases to the sample. There was minimal variation of this average among the
states, with most of the medians between 34 and 35. The State of Sergipe showed the highest
average, reaching a median of 35 cm.

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 Publication: Bulletin of the World Health Organization; Type: Research in emergencies
Article ID: BLT.16.171215
Table 1. Percentiles of cephalic perimeter measured at birth in states of the northeast
region of Brazil, 2007

Cephalic
Percentiles
perimeter (cm) CI 95%
5 31.0 30.63 - 31.37
10 32.0 31.82 - 32.18
25 33.0 33.00 - 33.00
50 34.0 33.94 - 34.06
75 36.0 35.12 - 36.88
90 37.0 36.89 - 37.11
95 38.0 37.33 - 38.67

The average cephalic perimeter was 34 cm, and the point of 32 cm for the diagnosis of
microcephaly corresponded to P10 in this population, with a confidence interval between
31.82 and 32.18. The cephalic perimeter of 33 cm, considered earlier in Brazil, corresponded
to the first quartile.

Table 2. Incidence of microcephaly1 within six months in different states of the northeast
Region of Brazil, 2007.

Microcefalia
No Sim
Estados
N % N %
Sergipe 53 93.00% 4 7.00%
Cear 213 93.80% 14 6.20%
Paraba 114 95.80% 5 4.20%
Piau 54 96.40% 2 3.60%
Bahia 149 96.80% 5 3.20%
Maranho 246 97.20% 7 2.80%
Alagoas 106 99.10% 1 0.90%
Rio Grande do Norte 23 100.00% 0 0.00%
Regio Nordeste 958 96.2% 38 2.8%
1
Defined as cephalic perimeter less than 2 standard deviations.

In three states, Alagoas, Rio Grande do Norte and Sergipe, there was practically no incidence
of cases of microcephaly on the six-month period studied, different from other states, where
the prevalence ranged from 3.2 to 7.0%. For the northeast region as a whole, the incidence
was 2.8%.

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 Publication: Bulletin of the World Health Organization; Type: Research in emergencies
Article ID: BLT.16.171215
Table 3 lists the main risk factors for microcephaly between children born between 37 to 41
weeks.
Table 3. Bivariate analysis of associated factors of microcephaly in new-borns within 37
a 41 weeks of gestation in the northeast region of Brazil, 2007
Microcephaly
Yes No
n % n % OR 95%CI p value
Maternal factors
Hypertension No 33 4.1% 765 95.9% 1.11 0.84-1.47 0.124
Yes 0 0.0% 55 100.0% 1 - -
Previous diabetes Yes 0 0.0% 10 100.0% 0.60 0.28-1.29 0.189
No 31 3.8% 784 96.2% 1 - -
Did prenatal care No 6 6.0% 94 94.0% 1.59 1.30-1.96 <0.001
Yes 30 3.4% 850 96.6% 1 - -
Gestational Factors
Pre-eclampsia Yes 5 4.5% 107 95.5% 1.24 1.04-1.48 0.021
No 28 3.7% 728 96.3% 1 - -
Eclampsia Yes 1 4.8% 20 95.2% 1.94 1.41-2.67 <0.001
No 31 3.7% 817 96.3% 1 - -
Gestacional diabetes No 29 3.6% 780 96.4% 0.31 0.16-0.59 <0.001
Yes 1 4.0% 24 96.0% 1 - -
Urinary tract infection Yes 10 4.3% 222 95.7% 1.01 0.85-1.18 0.617
No 21 3.6% 567 96.4% 1 - -
HIV Yes 1 16.7% 5 83.3% 1.37 0.64-2.98 0.103
No 27 3.8% 690 96.2% 1 - -
HBsAg No 21 4.1% 497 95.9% 1.74 0.69-4.35 0.235
Yes 0 0.0% 4 100.0% 1 - -
Syphilis Yes 0 0.0% 16 100.0% 0.78 0.41-1.47 0.439
No 27 3.6% 727 96.4% 1 - -
Toxoplasmosis Yes 2 11.8% 15 88.2% 2.52 1.84-3.43 <0.001
No 18 3.6% 486 96.4% 1 - -
Corticosteroids Yes, complete 1 14.3% 6 85.7% 3.87 3.15-4.74 <0.001
antenatal use Yes, incomplete 7 24.1% 22 75.9% 4.93 3.74-6.49 <0.001
No 23 2.9% 766 97.1% 1 - -
Chorioamnionitis Yes 1 3.7% 26 96.3% 2.22 1.64-3.00 <0.001
No 28 3.5% 771 96.5% 1 - -
Fetal distress Yes 5 2.7% 177 97.3% 0.93 0.78-1.11 0.418
No 24 3.6% 647 96.4% 1 - -
Oligohydramnios No 25 3.2% 746 96.8% 7.41 0.65-83.5 0.017
Yes 6 9.0% 61 91.0% 1 - -
Restriction of intra Yes 10 20.8% 38 79.2% 2.59 2.00-3.36 <0.001
uterine growth No 20 2.5% 784 97.5% 1 - -
Premature rupture of Yes 7 4.5% 147 95.5% 1.75 1.50-2.04 <0.001
membranes No 23 3.3% 684 96.7% 1 - -
Delivery factors
Preterm labor Yes 9 15.8% 48 84.2% 4.58 3.95-5.32 <0.001
No 24 2.9% 812 97.1% 1 - -
Premature placental Yes 2 9.5% 19 90.5% 1.80 1.38-2.36 <0.001
detachment No 29 3.4% 818 96.6% 1 - -
Oxytocin use Yes 5 4.1% 116 95.9% 0.75 0.59-0.94 0.014
No 11 5.0% 209 95.0% 1 - -
Type of delivery Vaginal cephalic 20 4.5% 421 95.5% 2.51 1.69-3.70 <0.001
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Article ID: BLT.16.171215
Vaginal pelvic 0 0.0% 12 100.0% 0 - 0.998
Caesarean 17 3.3% 497 96.7% 0.64 0.56-0.74 <0.001
Forceps 0 0.0% 16 100.0% 1 - -
Twin No 37 3.8% 944 96.2% 2.23 1.77-2.80 <0.001
Yes 1 6.7% 14 93.3% 1 - -
It has partogram Yes, other 1 1.0% 104 99.0% 0.83 0.69-0.98 0.028
Yes, from Health 15 5.5% 260 94.5% 0.68 0.53-0.88 0.003
Ministry
No 11 3.9% 268 96.1% 1 - -
Biological factors
Newborn gender Masculino 14 2.3% 583 97.7% 0.64 0.56-0.73 <0.001
Feminino 24 6.0% 375 94.0% 1 - -
Race 1 4 3.3% 118 96.7% 1.21 0.34-4.35 0.768
2 3 4.8% 59 95.2% 1.49 0.41-5.43 0.550
3 22 3.9% 544 96.1% 1.21 0.34-4.29 0.771
4 0 0.0% 5 100.0% 1 - -
Congenital anomaly No 24 3.1% 754 96.9% 0.38 0.28-0.53 <0.001
Yes 8 9.1% 80 90.9% 1 - -

Bivariate analysis showed an association with microcephaly in the following factors:

oligohydramnios (OR = 7.41; 95% CI 0.65-83.5, p = 0.017), premature labour (OR = 4.58;
95%CI 3.95-5.32), use of corticosteroid ante-natal ultrasound (OR = 3.87; 95%CI 3.15-4.74),
intrauterine growth restriction (OR = 2.59; 95%CI 2.00-3.36), positive test for toxoplasmosis
(OR = 2.52; 95% CI 1.84-3.43), new-born of the female gender (OR = 1.56; 95% CI 1.37-
1.78), and congenital anomalies (OR = 0.38; 95% CI 0.28-0.53).

Maternal infections with syphilis, hepatitis B and HIV showed no statistically

significant risk for microcephaly, only toxoplasmosis.

Table 4. Average and standard deviation of the selected maternal parameters, according
to the diagnosis of microcephaly in new-borns at 37 to 41 weeks of gestation in the
north-eastern region of Brazil, 2007

Microcefalia
Sim No
Mdia SD Mdia SD p
Maternal age 25 7 25 7 0.809
Maternal educacional years 6 3 7 4 0.259
Number of pregnancies 2 2 2 2 0.689
Number of abortations 0 1 0 1 0.591
Number of children born alive 1 2 1 1 0.750
Number of stillbirths 0 0 0 0 0.787
Number of prenatal visits 5 2 6 2 0.278
gestational age in weeks in the 1st prenatal visit 15 7 15 8 0.748

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Article ID: BLT.16.171215
The average and standard deviation of factors such as maternal age and education,
reproductive background and prenatal care attendance were compared among infants with and
without microcephaly but did not show any statistically significant association.

Table 5. Adjusted analysis of the factors associated with microcephaly in new-borns at

37 to 41 weeks of gestation in the north-eastern region of Brazil, 2007

Microcephaly
Yes No

OR 95%CI ORa 95%CI p

Yes 2.59 2.00-3.36 8.77 2.56-30.1 0.001

Restriction of intra uterine growth
No 1 -

Yes, completo 3.87 3.15-4.74 4.826 1.07-21.8 0.041

Corticosteroids antenatal use
Yes, incompleto 4.93 3.74-6.49
No 1 -

Congenital anomaly Yes 2,63 1.89-3.57 3.873 1.08-13.9 0.038

No 1 -

Oligohydramnios Yes 7.41 0.65-83.5 3.77 1.10-12.9 0.034

No 1 -

1
Controlled by: premature labour, congenital anomalies, gender of the new-born, meconium
in the amniotic fluid, positive maternal HIV tests.

Intrauterine growth restriction, defined in this study as weight less than the tenth percentile of
expected at some point in pregnancy, has appeared as the main risk factor for microcephaly,
with new-borns who have suffered from this condition presenting a risk adjusted 8.77 (95%
CI 2.56-30.1) greater of microcephaly, compared with children without this condition.
Pregnancies resulting in congenital anomalies and oligohydramnios were also strongly
associated with microcephaly, with high risks similar to 3.87 and 3.77, respectively.
The maternal use of steroids is also strongly associated with microcephaly, with children
whose mothers made use of this medication during pregnancy featuring a 4.83 times greater
risk (95% CI 1.07-21.8) of microcephaly than children who were not exposed to this type of
drug.

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Article ID: BLT.16.171215
Discussion

This study suggests measures to be used as cut-offs that could be considered normal for the
cephalic perimeter as well as factors that may contribute to the manifestation of microcephaly
in new-borns.
Brazil has experienced an outbreak of cases of children identified with microcephaly (1), with
more than 2000 cases already registered. Microcephaly is a rare condition, with an estimated
prevalence of 1.9% (16). The incidence during the most current outbreak in one of the states
of Brazil, Pernambuco, was approximately 4%. The first step for public strategies to confront
this pathology is proper diagnosis. The Brazilian government is still working on the definition
of the ideal cut-off point; the initial use of 33 cm as the cut-off cephalic perimeter for new-
borns of gestational age between 37 and 41 weeks has been modified, establishing a new less
sensitive cut-off point of 32 cm (4).
Considering that the diagnosis of microcephaly depends on a cephalic perimeter less than the
second standard deviation of the normal curve of the population (17), it is reasonable to use
the 5% percentile as the cut-off point for diagnosis. The percentile of 5% found in the sample
studied in this work, with more than 1000 individuals, was 31 cm, with a confidence interval
between 30.6 and 31.4 and a small variation between the different states.
Microcephaly can represent the structural deficiency of cerebral neurons or dendrites, and
depending on its development, it can be primary or secondary, changing its prognosis (5).
Most patients identified as carriers of microcephaly do not have a confirmed aetiologic
diagnosis (3).
Recently, genetic causes and mutations have been associated with cases of microcephaly as
their main determining factors (3, 18-20). This work identified that congenital anomalies were
independently associated with microcephaly, but they did not constitute the most important
factor. Intrauterine growth restriction has increased the risk of development of microcephaly
by about eight times. This association was found in a follow-up study conducted in Canada
(7), and it was identified that when both conditions are present and there is no recovery of the
cephalic perimeter, the prognosis for a child's development is reserved. Oligohydramnios is a
sign associated with a wide range of genetic diseases (21) and may be caused by many genetic
anomalies.
Infectious causes have not been independently associated with the diagnosis of microcephaly
in this work, unlike other studies, in which cytomegalovirus infection was significantly
associated (10). However, the identification of an association in bivariate analysis with
toxoplasmosis and the tendency towards association with HIN infection can justify further
studies in this field.
The use of steroids during pregnancy, especially in early stages of pregnancy, appears to have
effects on the foetus and on dose dependence (22). Animal models indicate that the use of
corticosteroids during pregnancy are associated with cognitive and behavioural changes (23).
In addition, an Australian cohort study identified that the use of antenatal corticosteroids may
reduce the cephalic perimeter by up to 4% (24). A meta-analysis in 2015 suggested that use
may lead to damage in the development of the new-born (25). This study adds to this body of
knowledge, favouring the association suggested, which may serve as a basis for future work.
It is noteworthy that while the first three factors, intrauterine growth restriction, congenital
anomalies and oligohydramnios, are pathological conditions of pregnancy intrinsically
correlated to the development of the braincase and its content, resulting in a predictably high
level of risk, the fourth factor, the use of steroids during pregnancy, presents itself as an
external condition, which suggests serious side effects of therapy with pharmacological
mechanisms that merits investigation.
In short, this work raises discussion on the cut-off point used for the diagnosis of
microcephaly at a population level in a country with an outbreak as well as factors that can be
associated with the outcome presented, particularly a factor that is potentially modifiable.
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