diseases in twins - fetofetal transfusion - child development - risk factors
doenças em gêmeos - transfusão feto-fetal - desenvolvimento infantil - fatores de
risco
Twin-twin transfusion syndrome (TTTS) is a serious condition that affects 9% to 15%
of all monochorionic diamniotic twin pregnancies[1], and typically develops between 15 and 26 weeks of gestation[2]. The syndrome is characterized by an unbalanced transfusion of blood across placental
vascular anastomoses from one twin (donor) to the other (recipient)[2]
,
[3]
,
[4]. Because of abnormal placental anastomoses, the donor pumps blood into the recipient.
The donor twin becomes hypovolemic, with resultant oliguria, oligohydramnios, and
sometimes growth restriction. The recipient becomes hypervolemic, with polyuria, polyhydramnios,
and cardiac dysfunction[3].
Untreated, the risk of fetal death is approximately 90%[3]
,
[4]. The optimal treatment for TTTS is fetoscopic laser coagulation (FLC) of placental
anastomoses, which has led to improved single and dual twin survival. With this improvement
in survival, there is a concern regarding risk factors to the neonatal neurologic
status and later neurodevelopmental outcome[5]
,
[6].
Fetoscopic laser coagulation interrupts the blood flow between the fetuses and reducing
the potential for major neurodevelopmental disability in survivors[7]
,
[8]. Nevertheless, neurologic morbidity rates after antenatal treatment remain high
(15% to 26%)[1]. It is important to emphasize that information about the effects of TTTS in the
infant development are still scarce, and risk factors associated with neurodevelopment
impairment have not yet been established[1]
,
[7]
,
[9]
,
[10].
With this in mind, the questions posed by the present study were: what is the developmental
profile of infants who suffered from TTTS? What are the factors that influenced the
infant development? In order to answer these questions, the present study aimed to
assess the neurodevelopmental functions (cognition, language and motor function) of
survivors of TTTS treated by FLC during the first year of life, comparing them to
a control group (full-term infants of single-fetus pregnancies); and to verify the
influence of specific variables on neurodevelopment.
It was hypothesized that detailed assessment during the first months of life would
provide important information for identifying early developmental disadvantages in
TTTS infants. Considering that there are few studies that have documented in detail
the long-term outcome of TTTS pregnancies, this study contributes to increase the
current knowledge about neurodevelopment of an understudied group, and discusses possible
clinical perspectives of early detection.
METHOD
The research design was an observational, prospective, longitudinal study of monochorionic
diamniotic twins who underwent FLC for treatment of TTTS, compared to full-term infants
of single-fetus pregnancies, with birth weight appropriate for gestational age during
the first year of life. This project was approved by the Research Ethics Committee
of the Medical School of the State University of Campinas (UNICAMP) (process no 935/2011).
Infants were selected using the following inclusion criteria: 1) infants from monochorionic
diamniotic twin pregnancies who had TTTS stages I, II, III or IV according to the
classification of Quintero et al.[11] and underwent FLC, composing the study group (TTTS group); 2) the control group
was composed of infants born at the Neonatology Service of the Center of Integral
Attention to Women’s Health – UNICAMP, of single-fetus pregnancies, considered to
be in good health allowing them to go home within two days of birth, with gestational
age categorized as full-term (37–41 weeks) according to the Capurro method, and showing
expected birth weight appropriate for gestational age (between the 10th and 90th percentiles)
according to the Alexander method; 3) parents agreed to sign the informed consent;
and, 4) infants who were between one month and 12 months of age. Infants who presented
with any other malformation unrelated to TTTS were excluded. Considering that we do
not have validated Bayley scales, third edition in Brazil, we included a control group
of normal infants, to observe the behavior of Brazilian infants with the scale. Our
aim was to create a comparison group that might represent Brazilian infants (as much
as possible). We considered that we would have a more reliable instrument after that.
All FLC procedures were performed by the same surgeon (CFAP, who had seven years experience
in fetoscopic laser surgeries) at the Professor José Aristodemo Pinotti Hospital,
from 2009 to 2012, according to the endoscopic laser dichorionization of the placenta
procedure. The placental chorionic plate vessels were initially mapped through the
amniotic sac of the recipient twin; the vascular equator was identified; a line of
ablation of the chorionic plate was created from one edge of the placenta to the other,
including the arterio-venous anastomoses and vessels with unknown courses (those crossing
the inter-twin membrane from the recipient to the donor side and concealed behind
the fixed twin). Caution was taken to preserve the vessels originating from and returning
to the same fetus, which were surrounded by this line of ablation. At the end of the
photocoagulation process, polyhydramnios fluid was drained through the fetoscopy sheath
so that the deepest amniotic fluid pocket was less than 8 cm deep.
From initial selected sample (40), 33 infants (82.5%) survived after laser treatment
and participated in this study. Development was assessed using the Bayley Scales of
Infant and Toddler Development Screening Test, third edition[12], which included 33 items for testing cognition, 24 items for receptive communication,
24 items for expressive communication, 27 items for fine motor skills and 28 items
for gross motor skills.
Each subtest (cognition, receptive language, expressive language, gross motor and
fine motor skills) has a starting point consistent with the age or adjusted to the
child’s age. Every child is given an item score of zero or one. A zero score (0) refers
to a child who did not carry out the item or failed to meet the criteria established
by the test. The score of one (1) refers to a child who met the criteria established
by the test, showing adequate performance on the item.
To start the test, the child is required to achieve a score of one (1) on the first
item of his/her starting point previously determined by chronological or adjusted
age. The reversal rule is applied when the child is given zero (0) in the first item,
requiring the examiner to revert to the previous starting point. The test is completed
when the child receives four consecutive zeros.
At the end of the assessment a raw score is obtained for each subtest, which classifies
children into three categories: competent (low risk for delay), emerging (requires
subsequent reviews) and risk (should be referred for diagnostic assessment)[12]. To perform statistical analyses, the three categories of the Bayley Scale were
grouped into two types of responses: appropriate responses (consisting of the competent
category), and inadequate responses (comprising emerging and risk categories).
Neurological examination was performed by a pediatric neurologist following our standard
protocol[13].
The infants were assessed at the Center for Investigation in Pediatrics of UNICAMP
from July, 2011 to July, 2013. The infants were evaluated twice, at the age of one
to six months for the first evaluation and seven to 12 months for the second evaluation.
The adjusted age for prematurity was considered in the neurodevelopmental assessments,
using 40 weeks of gestation as a reference. The testers included a developmental neurologist
and three physiotherapists. Infants who presented with developmental disorders were
referred to a program for habilitation/rehabilitation.
Prenatal, perinatal and postnatal information were obtained through medical records
and parent interviews. The following data were recorded: TTTS classification (donor
or recipients), TTTS stage (I or II/III/IV), gestational age at surgery, type of delivery
(vaginal or cesarean), gender (female or male), fetal growth (SGA or AGA), gestational
age at delivery (pre-term or at term), Apgar score at first and fifth minutes (< 7
or ≥ 7), cardiorespiratory disease (present or absent), oxygen administration (present
or absent), maternal education (< 9 or ≥ 9), maternal occupation (work outside or
work at home), marital status (without partner or with partner), maternal age, number
of children and adults in the home, and economic class according to the Brazilian
Association of Research Companies[14], an instrument of economic segmentation that uses the survey of household characteristics
(presence and number of household items and education of the household head) to differentiate
the population. The criterion assigns points according to each household characteristic.
At the end of the questionnaire, a total score is obtained, which classifies families
into eight categories: A1, A2, B1, B2, C1, C2, D, E[14].
Statistical analyses were performed using the Statistical Analysis System (SAS 9.2).
The probability level adopted for rejection of the null hypothesis was p < 0.05. The
data were presented using position and dispersion measurements for numerical variables
and frequencies for categorical variables. The comparison of categorical variables
between groups was investigated with the Chi-Square or Fisher’s Exact Tests. The comparison
of paired proportions was examined with McNemar Test. Multiple logistic regression
analysis with “stepwise criterion of variable selection” was used to measure the independent
effects of prenatal, perinatal and postnatal factors on infant development of TTTS
group.
RESULTS
We present an observational, prospective, longitudinal study of 55 infants (33 infants
in the TTTS group and 22 infants in the control group). The mean age of the infants
in the first and second assessment were 5.5 (± 1.4) and 9.8 (± 1.9) months respectively.
The descriptive analysis of the characteristics of the two groups is presented in
[Table 1]. In the TTTS group the mean birth weight was 1671 grams (± 689.3) and the mean gestational
age was 32.4 weeks (± 3.5). Following the Quintero classification, 5 children were
classified in stage I (15.2%), 4 in stage II (12.1%), 18 in stage III (54.5%) and
6 in stage IV (18.2%). In the control group, the mean birth weight was 3387.9 grams
(± 285.8), and the mean gestational age was 39.2 weeks (± 0.9). Considering the family
characteristics, in the TTTS and control groups, there was a greater frequency of
mothers who had low income (around US$ 1840 for the TTTS group and US$ 1068 for the
control group).
Table 1
Demographic characteristics of the two groups.
|
Variables
|
TTTS group
|
Control group
|
|
TTTS classification – Recipients
|
19 (57.6%)
|
N/A
|
|
Quintero stage – II / III / IV
|
28 (84.9%)
|
N/A
|
|
Mode of delivery – Cesarean
|
32 (97.0%)
|
6 (27.3%)
|
|
Gender – Female
|
22 (66.7%)
|
15 (68.2%)
|
|
Fetal growth – AGA
|
19 (57.6%)
|
22 (100%)
|
|
Gestational age at birth – Pre-term
|
29 (87.9%)
|
0
|
|
Apgar score
|
|
|
|
|
|
1st – ≥ 7
|
27 (81.8%)
|
22 (100%)
|
|
5th – ≥ 7
|
31 (93.9%)
|
22 (100%)
|
|
Present
|
|
|
|
|
|
Cardiorespiratory disease
|
20 (62.5%)
|
5 (22.7%)
|
|
Oxygen administration
|
21 (63.6%)
|
0
|
|
Maternal education (years) – ≥ 9
|
30 (90.9%)
|
17 (77.3%)
|
|
Maternal occupation – Work at home
|
17 (51.5%)
|
15 (68.2%)
|
|
Marital status – with partner
|
31 (93.9%)
|
16 (72.7%)
|
|
Numeric variable
|
Mean
|
SD
|
Mean
|
SD
|
|
Gestational age at surgery (weeks)
|
21.2
|
1.9
|
N/A
|
|
Maternal age (years)
|
29.5
|
6.3
|
25.2
|
7.8
|
|
Number of children in the home
|
2.5
|
0.9
|
1.4
|
0.6
|
|
Number of adults in the home
|
2.8
|
1.1
|
3.0
|
1.1
|
|
Economic class (score)
|
29.9
|
7.9
|
24.6
|
0.6
|
SD: standard deviation; TTTS: twin-twin transfusion syndrome; AGA: .
All infants of the TTTS group underwent neurological examination, which revealed three
infants with strabismus (9.1%), one infant with microcephaly (3.0%), and six infants
with spastic cerebral palsy (18.1%), four of them with tetraparesis and two with diparesis.
[Table 2] describes in more detail the situation of each infant with cerebral palsy. Most
infants were graded as severe by Quintero classification (III), were small for gestational
age, and had Apgar scores at one minute ≤ 7.
Table 2
Characteristics of infants diagnosed with cerebral palsy.
|
Infants with cerebral palsy
|
TTTS classification
|
Quintero stage
|
Gestational age at surgery (weeks)
|
Gestational age at birth (weeks)
|
Fetal growth
|
Apgar 1
|
Apgar 5
|
|
1
|
donor
|
III
|
22.0
|
34.1
|
SGA
|
8
|
9
|
|
2
|
donor
|
III
|
19.4
|
28.0
|
SGA
|
6
|
9
|
|
3
|
donor
|
III
|
21.1
|
33.4
|
SGA
|
7
|
8
|
|
4
|
recipients
|
IV
|
25.0
|
26.4
|
AGA
|
6
|
8
|
|
5
|
recipients
|
III
|
17.0
|
28.4
|
AGA
|
8
|
9
|
|
6
|
recipients
|
III
|
20.0
|
27.6
|
SGA
|
7
|
8
|
TTTS: twin-twin transfusion syndrome; SGA: ; AGA; .
Regarding the assessment with the Bayley Scales, most infants were classified as appropriate
for development. In our study the frequency of inappropriate performance in both evaluations
for the TTTS group was around 18.2% for the cognitive domain, 9.1% for receptive communication,
21.2% for expressive communication, 24.2% for fine motor and 24.2% for gross motor
skills. [Tables 3] and [4] show comparative analysis between the groups in the first and second assessments
respectively. In the first assessment, there were significant differences between
the groups only in the cognitive and fine motor domains. In the second assessment,
there were significant differences between the groups in all domains (cognitive, receptive
and expressive communication, gross and fine motor skills). In both evaluations there
were more infants in the TTTS group with inadequate performance in relation to the
control group. We found no significant differences in neurodevelopmental outcomes
between the first and second assessment of the TTTS group.
Table 3
Comparative analysis between groups in the first assessment.
|
Domains
|
TTTS Group
|
Control Group
|
p-value
|
|
|
Inadequate
|
Appropriate
|
Inadequate
|
Appropriate
|
|
Cognition
|
10 (30.3%)
|
23 (69.7%)
|
0
|
22 (100%)
|
0.003*
|
|
Receptive communication
|
05 (15.1%)
|
28 (84.9%)
|
01 (4.6%)
|
21 (95.4%)
|
0.384*
|
|
Expressive communication
|
11 (33.3%)
|
22 (66.7%)
|
09 (40.9%)
|
13 (59.1%)
|
0.567**
|
|
Gross motor
|
14 (42.4%)
|
19 (57.6%)
|
04 (18.2%)
|
18 (81.8%)
|
0.060**
|
|
Fine motor
|
16 (48.5%)
|
17 (51.5%)
|
02 (9.1%)
|
20 (90.9%)
|
0.002**
|
TTTS: twin-twin transfusion syndrome; * Fisher’s exact test; **Chi-Square test.
Table 4
Comparative analysis between groups in the second assessment.
|
Domains
|
TTTS Group
|
Control Group
|
p-value
|
|
|
Inadequate
|
Appropriate
|
Inadequate
|
Appropriate
|
|
Cognition
|
10 (30.3%)
|
23 (69.7%)
|
0
|
22 (100%)
|
0.003*
|
|
Receptive communication
|
05 (15.1%)
|
28 (84.9%)
|
01 (4.6%)
|
21 (95.4%)
|
0.384*
|
|
Expressive communication
|
11 (33.3%)
|
22 (66.7%)
|
09 (40.9%)
|
13 (59.1%)
|
0.567**
|
|
Gross motor
|
14 (42.4%)
|
19 (57.6%)
|
04 (18.2%)
|
18 (81.8%)
|
0.060**
|
|
Fine motor
|
16 (48.5%)
|
17 (51.5%)
|
02 (9.1%)
|
20 (90.9%)
|
0.002**
|
TTTS: twin-twin transfusion syndrome; *Fisher’s exact test; **Chi-Square test. Domains.
Multiple logistic regressions were carried out to measure the association between
neurodevelopment and various clinical parameters. The analysis revealed that TTTS
classification (OR 6.8, 95%CI 1.0–44.6, p = 0.04) and economic class (OR 1.1, 95%CI
1.0–1.3, p = 0.01) were significantly associated with expressive communication. Infants
classified as donors in TTTS had a higher risk of abnormality (6.8 times) than the
recipients; and infants whose families had a lower economic score displayed a higher
risk of abnormality (each point decreases the risk of abnormality by 16.0%). Moreover
it was found that the cardiorespiratory disease variable (OR 5.6, 95%CI 1.1–27.5,
p = 0.03) was significantly associated with fine motor function. Infants with cardiorespiratory
disease had a higher risk of abnormality (5.6 times) than those without the disease.
The TTTS Quintero stage, gestational age at surgery, type of delivery, gender, fetal
growth, gestational age at delivery, Apgar score at first and fifth minutes, oxygen
administration, maternal education, maternal occupation, marital status, maternal
age, number of children and adults at home were not risk factors for neurodevelopmental
outcomes.
DISCUSSION
The focus of the present study was to assess the neurodevelopmental functions (cognition,
language and motor function) of survivors of TTTS treated by FLC, and to verify the
influence of specific variables on neurodevelopment. We were able to follow up the
TTTS group during the first year of life, and compared them to a control group.
Our data showed a high rate of normal neurodevelopmental outcome in a group of infants
who were treated for TTTS by FLC. This fact suggests that, although infants with TTTS
have a high risk of morbidity, FLC treatment was an effective procedure to allow normal
development in most infants[8]. The frequency of inappropriate performance in both evaluations for the TTTS group
was around 18.2% for the cognitive domain, 9.1% for receptive communication, 21.2%
for expressive communication, 24.2% for fine motor and 24.2% for gross motor skills.
We also found six infants in our cohort who could be diagnosed as having cerebral
palsy.
The neurodevelopmental outcome found in this study is in agreement with other outcome
reported previously. The prevalence of cerebral palsy associated with TTTS managed
with FLC has been reported to be 3%–16% and the prevalence of neurodevelopmental disabilities
to be 12%–33%[1]
,
[6]
,
[7]
,
[9]
,
[15]
,
[16]
,
[17]. The discrepancies in reported rates may partly be due to several methodological
differences such as the use of different protocols and criteria for the definition
of cerebral injury and neurodevelopmental impairment, including clinical or imaging
scans at different ages[6]
,
[18]
,
[19].
The comparative analysis between groups showed significant differences at the first
and second assessment. There was increased frequency of infants in the TTTS group
with inadequate performance in relation to control group. These results are not surprising.
Large population-based studies consistently show that the long-term neurodevelopmental
outcomes of twins are worse than those of singletons[16]. Language and speech delays are more pronounced in multiples, as are cognitive delays,
motor development, behavioral problems and difficulties in parent-child interactions[20]. In multiple gestations, factors such as preeclampsia, TTTS, and the competition
between multiple infants for placental nutrient and oxygen delivery seem to place
the twins at risk for growth and development problems[21]. TTTS is a well-recognized risk factor for adverse neurodevelopment outcome[9], and appears to be associated with an increase in long-term cognitive and neuromotor
disabilities[16]. The exact mechanism responsible for neurodevelopmental deviation in infants who
suffered from TTTS is not clear. The brain injury may result from hemodynamic imbalance
and intertwin blood shifts, which lead to hypoxic-ischemic insults during pregnancy,
or from postnatal injury associated with prematurity and low birth weight[6].
Multiple risk factors can increase the risk of developmental disability, by either
additive or multiplicative effects. Genetic factors, nutrition, health, environment
in which the children grow up, and opportunities offered by their families are all
determinants of child development[22]
-
[24].
It seems that donor and recipient twins with TTTS treated with FLC are equally at
risk for cerebral injury and long-term neurodevelopment impairment[2]
,
[4]
,
[9]. However, our results showed an independent association between expressive communication
disturbance and donor infants. This should be explored in following studies. Similar
to our results Tosello[1] suggested that the risk of neurosensory sequel was significantly related to the
status of donor. It is known that donor twins are significantly smaller at birth than
recipient twins and remain shorter at two years of age[18]. Lower birth weight has been associated with an increased risk for developmental
disturbance[25].So, this fact may have contributed to worse performance of donor twins in relation
to recipient twins.
In the present study, the infants whose families had lower economic income showed
a higher risk of expressive communication disturbance. These findings are in agreement
with prior research, which has demonstrated strong associations between familial socioeconomic
resources and children’s health outcome, with especially poor health outcome among
disadvantaged youth who experience a concentration of risks[26]. Children from middle and low-income countries face an even greater challenge: in
addition to being more susceptible to perinatal problems, these children are also
subject to unfavorable household environments, in which stimulation and social support
are inadequate. This combination of events increases the risk of problems in cognitive,
physical, and social development[27].
Another issue that needs to be addressed is the effect of cardiorespiratory disease
on infant development. In the present study infants with cardiorespiratory disease
had a higher risk of fine motor disturbance than those without the disease. The abnormal
placenta that occurs in cases that develop TTTS contributes to abnormal fetal heart
formation, primarily in recipient twins, such as ventricular hypertrophy, atrioventricular
valve regurgitation, and abnormal right ventricular or left ventricular function.
These cardiac abnormalities can contribute to the poor neurodevelopmental outcome[17]. Likewise, it has been suggested that children who develop chronic lung disease
may be developmentally compromised by exposure to hypoxic episodes[28] and have abnormal motor outcome at one year[29] and at school-going age[30]. According to the authors, early assessment and motor therapy is recommended for
infants with chronic lung disease, because of its effect on motor performance.
The present study has certain limitations that should be taken into account when considering
its possible contributions. First, the sample was small; this fact could have influenced
the results, at least in part. A larger sample should be considered in future research.
Second, we used a non-standard assessment tool for the Brazilian population. However,
the Bayley Scales have an overall acceptance, and we included a control group to observe
the behavior of Brazilian infants with the scale. Third, we use a control group absolutely
no risk, full-term infants of single-fetus pregnancies. Future researches should use
a control group of infants from twin pregnancies without TTTS, matched for gestational
age.
This study represents one of the few studies addressing the neurodevelopmental functions
of monochorionic diamniotic twins who underwent FLC for treatment of TTTS. Our study
was conducted during the first year of life and included a control group. We identified
three variables that jeopardize the outcome. Infants classified as donors and infants
whose families had lower economic income showed higher risk for expressive communication
disturbance. Moreover, infants with cardiorespiratory disease had a higher risk for
fine motor disturbance.
In conclusion, we were able to establish specific variables (fetal donor, lower economic
income and presence of cardiorespiratory disease) for neurodevelopment impairment
in survivors of TTTS after FLC. Although thorough follow-up is recommended in all
TTTS survivors, particular attention is required for the high-risk group as defined
in this study.
