the long term neurologic outcome of children from pregnancies complicated by twin-to-twin...

The long term neurologic outcome of children from pregnanciescomplicated by twin-to-twin transfusion syndrome

Jan E. Dickinson,a Gregory J. Duncombe,b Sharon F. Evans,a

Noel P. French,a Ronnie Hagana

Objective To assess long term outcomes of children from pregnancies complicated by twin-to-twin transfusionsyndrome.

Design Comparison of children from pregnancies with twin-to-twin transfusion syndrome in Western Australiawith a contemporaneous regional comparison cohort of preterm and term infants studied using an identicalassessment procedure.

Population and setting All infants aged �18 months were identified from a geographically based longitudinalcohort of monochorionic twin pregnancies with an antenatal diagnosis of twin-to-twin transfusion syndromeconducted prospectively since 1992.

Methods Children were evaluated using age-specific developmental and behavioural assessments. Cerebralpalsy was diagnosed clinically and ascertainment confirmed through the Western Australian Cerebral PalsyRegister.

Main outcome measures Intellectual disability, cerebral palsy, behavioural and cognitive function.

Results Fifty-two children were identified as eligible for study and assessments were performed on 49 (94%).Three surviving children had a diagnosis of cerebral palsy (5.8%). The mean IQ score was 8 points lower intwin-to-twin transfusion syndrome children compared with the comparison cohort although this was mainlydue to a decrement of 13 points in those born before 33 weeks of gestation. There was no difference betweenthe donor and the recipient twin in terms of IQ scores (median difference �3, 95% CI �9 to 6). There wasno relationship of IQ score to the worst stage of the twin-to-twin transfusion syndrome. Child BehaviorCheck List and Vineland Adaptive Behavior Scale scores did not differ between twin-to-twin transfusionsyndrome children and the comparison group.

Conclusions Twin-to-twin transfusion syndrome is associated with a significant reduction in IQ score in verypreterm survivors. There seems to be no increase in the prevalence of cerebral palsy. Overall behaviour andadaptive behaviour scale scores are similar to a comparison group.

INTRODUCTION

Over the past two decades short term outcomes for

pregnancies complicated by twin-to-twin transfusion syn-

drome have improved from almost universal death to

survival rates of 50–70%.1 These improvements in peri-

natal survival have been secondary to obstetric interven-

tions such as serial amnioreduction2–4 and placental laser

ablation therapy,5–7 combined with advances in neo-

natal intensive care. Although perinatal survival rates

have improved, outcomes for twin-to-twin transfusion

syndrome are confounded by the impact of preterm birth

and abnormalities in fetal growth.8–12 The most com-

mon antenatal intervention for twin-to-twin transfusion

syndrome is serial amnioreduction, for which cases the

median gestation at delivery is 29–30 weeks.13,14 Clearly,

such very preterm birth is associated with significant neo-

natal complications and the possibility of long term dis-

ability. The incidence of major neonatal cranial ultrasound

abnormality has been reported as high as 20.9–24.3%

with an incidence of periventricular leucomalacia in peri-

natal survivors of 5.1–7.5%.13,14 Given the high morbidity

rates in the perinatal period, systematic study of the longer

term outcomes is required.

In 1992, a prospective longitudinal database of preg-

nancies complicated with twin-to-twin transfusion syn-

drome in Western Australia was established. Due to the

existence of a single tertiary referral centre for peri-

natal medicine in Western Australia, the unique oppor-

tunity to monitor and review all cases of prenatally

diagnosed twin-to-twin transfusion syndrome is now pos-

sible. The aims of this study were to (i) assess the long term

outcomes for all cases of monochorionic twin pregnancies

BJOG: an International Journal of Obstetrics and GynaecologyJanuary 2005, Vol. 112, pp. 63–68

D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology www.blackwellpublishing.com/bjog

aSchool of Women’s and Infants’ Health, The University of

Western Australia, AustraliabMater Mothers Hospital, Brisbane, Queensland, Australia

Correspondence: Dr J. Dickinson, School of Women’s and Infants’

Health, The University of Western Australia, 374 Bagot Road, Subiaco,

Western Australia, 6008, Australia.

DOI: 10.1111/ j .1471-0528.2004.00330.x

complicated by twin-to-twin transfusion syndrome, inde-

pendent of therapeutic intervention and (ii) contrast these

outcomes with a contemporaneous regional comparison

cohort.

METHODS

In 1992, a prospective cohort encompassing all cases of

prenatally diagnosed twin-to-twin transfusion syndrome

pregnancies was established at the Women and Infants

Research Foundation, Perth, Western Australia. The study

population for this manuscript includes all pregnancies

from this cohort during the period from May 1992 through

May 1999.

Obstetric and neonatal outcome data for all cases of

twin-to-twin transfusion syndrome have been collected

prospectively and maintained on the twin-to-twin transfu-

sion syndrome register since 1992. Diagnostic criteria,

patient characteristics and perinatal outcomes for this

population have been reported previously.15 This study

design involved the identification of all surviving children

aged at least 18 months from the twin-to-twin transfusion

syndrome cohort. Confirmation of survival was checked

through the Western Australian Registrar General’s Office

for notification of death. The residence of all surviving

children was identified using the statewide outpatient

appointment system database and the responsible physician

contacted the parents to ascertain willingness to participate

in the study. The Institutional Ethics Committee of King

Edward Memorial Hospital for Women provided permis-

sion for the conduct of this study.

Children were assessed using questionnaires and stand-

ardised psychological assessments. In addition, the children

born very preterm (<33 weeks) underwent neurologic

examination as did more mature infants where question-

naires or psychological assessments suggested possible

neurologic deficits. Questionnaires used were (i) gen-

eral health/demographic questionnaires, (ii) Vineland

Adaptive Behavior Scales (VABS)16 and (iii) The Child

Behavior Check List (CBCL).17 This VABS measures

behaviour in several domains relevant to the child’s func-

tion in their home environment (i.e. communication, daily

living skills, socialisation and motor function) as well

as an overall composite. The VABS was completed dur-

ing an interview with the child’s primary caregiver and

standardised scores were compared. The CBCL is a val-

idated questionnaire for parents to rate a wide range of

their child’s behaviours with responses being grouped in

six subscales. This study reports the total standardised

behavioural score (the sum of all six scales) and the ex-

ternalising score (the sum of aggressive and destructive

subscales). Problem behaviours were defined as those

where the total or aggressive/destructive scores were greater

than the 98th centile values for the Western Australian

population.

Psychological assessments usedwere the Bayley Scales of

Infant Development (BSID)18 for children below three years

of age, or the Stanford–Binet Intelligence Scale, Fourth

Edition, Australian Adaptation.19 Intellectual disability

was defined as either a Mental Development Index (MDI)

on the Bayley test or a Stanford–Binet Intelligence Score

more than two standard deviations below the Western

Australian comparison groups.

Cerebral palsy was defined clinically, based on findings

of increased muscle tone in the presence of functional

motor deficit. Completeness of cerebral palsy ascertain-

ment was confirmed by checking for cases against the West

Australian Cerebral Palsy Register. This statewide register

has multiple sources of data input from all clinical services

likely to provide services to children with disabilities, and

has been shown to have comprehensive cerebral palsy

ascertainment on a regional basis.

Infants from the twin-to-twin transfusion syndrome group

were compared with a large contemporaneous regional com-

parison cohort of infants on whom similar assessments had

been made at age three and six years of age. The majority of

these were infants born very preterm or of very low birth-

weight, and represented all such infants delivered in West

Australia from 1990 to mid 1992.20 The comparison cohort

also included 200 infants who were born at term and were

part of the Western Australian Pregnancy Cohort (Raine)

Study.21

Comparisons were performed in two phases. The first

phase was a multivariate analysis of variance to determine

any effect of being born as part of a pregnancy affected by

twin-to-twin transfusion syndrome, controlling for sex, ges-

tational age at birth, birthweight ratio, being part of a

multiple pregnancy and social class. In the second phase,

twin-to-twin transfusion syndrome children were compared

in a case–control manner with children from this compar-

ison cohort. Cases were matched on sex, gestational age,

birthweight ratio and social class. Two controls were sought

for each twin-to-twin transfusion syndrome child, the first

being part of a same-sex twin pair (twin control) and the

second being a singleton delivery (singleton control). Due to

difficulties in matching, only 27 twin controls were available

and these were at the very preterm end (<33 weeks) of the

gestational age range.

The data analyses were conducted using the SAS statis-

tical package version 8 (SAS Systems, Cary, North Caro-

lina, USA). Normally distributed continuous data were

expressed as mean and standard deviation, and otherwise

as median and interquartile range. Categorical variables

were expressed as n (%). Comparisons for the IQ variable

between the twin-to-twin transfusion syndrome group and

the regional cohort were made using analysis of variance

controlling for gestational age, sex and social class. For the

non-parametric data (CBCL, VABS) comparisons were

made using the Wilcoxon two-sample test. Outcomes for

twin-to-twin transfusion syndrome groups and matched

controls were compared using the paired Student’s t test

64 J.E. DICKINSON ET AL.

D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology 112, pp. 63–68

(IQ) and Wilcoxon matched pairs signed rank test (CBCL,

VABS). Adjusted differences with 95% confidence inter-

vals have been quoted for IQ measures, and median differ-

ences for behavioural measures. For all tests, a P value of

0.05 was considered to be statistically significant.

RESULTS

A total of 64 pregnancies complicated by twin-to-twin

transfusion syndrome occurred during the study period. In

13 pregnancies both fetuses were stillborn. In 44 pregnan-

cies, both fetuses were alive at birth and in seven pregnan-

cies only one fetus was born alive. A total of 81 neonates

survived to hospital discharge and one infant subsequently

died at six months of age from neurologic complications.

Twenty-eight twins were aged less than 18 months at the

time of the review, providing an eligible study population

of 52 children (21 pairs of twins and 10 single surviving

twin) from 31 pregnancies.

The perinatal outcomes for the 52 surviving children are

shown in Table 1. The majority of surviving children were

delivered preterm, with 52% delivered very preterm (<33

weeks of gestation). All pregnancies with at least one

survivor were >25 weeks of gestation at delivery. The

median duration of neonatal nursery admission was 37 days

(22, 54 days). Grade III or IV intraventricular haemorrhage

was present in four cases (7.7%) and cavitary periventric-

ular leucomalacia present in two cases (3.8%).

Forty-four of the eligible children were reviewed accord-

ing to the complete study protocol (85%) with five others

(9%) having partial assessments. Three children (6%) had

no outcome data due to loss of contact with two families

and one family declined participation (all single survivor

families). The median age of assessment for twin-to-twin

transfusion syndrome children was five years (3.3, 6.3

years), and for the comparison group was four years (3.2,

6.2 years). Eleven twin-to-twin transfusion syndrome chil-

dren were tested with the Bayley MDI and the remaining

33 were assessed with the Stanford–Binet Intelligence

Score, as were the entire comparison group. Clinical de-

tails of the comparison cohort and the selected controls are

shown in Table 2.

Cerebral palsy was present in three children (5.8%

overall) all of whom were independently ambulant. These

were manifest as diplegia (two cases) and hemiplegia (one

case). Thirty-two children were delivered very preterm at

<33 weeks of gestation, two of whom had cerebral palsy

Table 1. Antenatal and delivery characteristics of surviving children. Data

shown as median [interquartile range] or n (%) as appropriate.

No. of pregnancies 31

Gestation at diagnosis (weeks) 21.4 [20.1, 26.1]

Critically abnormal umbilical flow patterns# 8 (15.4)

Fetal hydrops of recipient at diagnosis 1 (3.2)

Use of amnioreduction 22 (71.0)

Amnioreduction per pregnancy (n ¼ 22) 3 [2, 4]

Diagnosis to delivery interval (weeks) 9.0 [2.6, 14.7]

Antenatal corticosteroids 27 (87.1)

Gestation at delivery (weeks) 32 [29.1, 36.3]

Caesarean section 17 (54.8)

Preterm birth

<33 weeks of gestation 16 (51.6)

<37 weeks of gestation 25 (80.7)

Birthweight (g)#

Recipient (n ¼ 27) 1730 [1265, 2460]

Donor (n ¼ 25) 1450 [940, 1700]

# Data are presented per child (52 surviving children).

Table 2. Clinical details. Values are presented as median (interquartile range).

Twin-to-twin cases Comparison groups

Regional cohort Matched controls#

Singletons Twins

n 52 1105 44 27

Gestational age (weeks) 32 (30, 36) 32 (30, 39) 32 (30, 36) 31 (29, 31)

Birthweight ratio 0.81 (0.68, 0.98) 0.99 (0.88, 1.1) 0.88 (0.74, 1.0) 0.91 (0.81, 1.0)

Social class 2.4 (1.5, 3.0) 2.4 (1.6, 3.0) 2.6 (1.4, 3.2) 2.2 (1.4, 3.2)

Male sex (%) 53 53

# Controls matched by sex, gestational age, birthweight ratio and social class from the regional cohort.

Table 3. Cognitive outcomes. Values are presented as mean [standard

deviation] unless otherwise indicated.

Twin-to-

twin cases

Comparison groups

Regional

cohort

Matched controls

Singletons Twins

n 44a 27b 1105 44 27

IQ score 95 [15] 91 [14] 103 [11] 104 [10] 104 [11]

IQ difference

(95% CI)

8 (4 to 11) 9 (4 to 14) 13 (6 to 20)

P# 0.0001 0.0021 0.0008

a Twin-to-twin transfusion subset matched with singleton controls.b Twin-to-twin transfusion subset matched with twin controls.# P value determined from linear regression adjusted for gestational age,

sex and social class (regional cohort) and paired t test (matched controls).

CHILDHOOD OUTCOMES IN TWIN-TO-TWIN TRANSFUSION SYNDROME 65


(6.3%, 95% CI 0.8 to 20.8). In the comparison cohort, the

prevalence of cerebral palsy in very preterm non-twin-to-

twin transfusion syndrome twins was 9/184 (4.9%, 95% CI

2.3 to 9.1) and in very preterm singletons 17/510 (3.3%,

95% CI 2.0 to 5.3). These rates were not statistically

significantly different.

Twin-to-twin transfusion syndrome children had a lower

score on cognitive tests with a significant interaction

between twin-to-twin status and gestational age (Table 3).

Very preterm twins in the twin-to-twin transfusion syn-

drome group had a 13-point difference in IQ scores,

whereas those at higher gestational ages had only a

three-point difference (Table 4). These differences were

confirmed in the case–control analyses. Six (14%) of the

twin-to-twin transfusion syndrome children had IQ scores

more than two standard deviations below the Western

Australian mean. There was no significant difference in

IQ scores between putative donor and recipient twins where

both had survived (median difference �3, 95% CI �9 to 6).

There was no relationship to the worst stage of the twin-

to-twin transfusion syndrome; stages 1–2: median 96

(90, 104); stage 3: 94 (87, 103); stages 4–5: 101 (79, 105).

There were no differences in any subscale score on the

CBCL or on any subscale of the VABS on either analysis

(Table 5). Five (12%) of twin-to-twin children had total

or externalising behaviour scores on the CBCL above the

98th centile indicative of a clinical behaviour problem.

Overall, disabilities were present in seven (14.3%) of twin-

to-twin transfusion syndrome children, with five having

intellectual disability, two having cerebral palsy only and

one with both. There were no cases of blindness or

deafness.

There was an antenatal demise of one twin with a single

surviving twin in six of the twin-to-twin transfusion syn-

drome cases. Within this group one child, delivered at

26 weeks, was lost to follow up. A further child, delivered

at 33 weeks, has cerebral palsy with the remaining four

single surviving twins having normal IQ scores [median IQ

105 (101, 109.5)] and behavioural assessments. In all cases,

the surviving twin was designated antenatally as the recip-

ient fetus. The four normal single surviving twins all were

Table 4. Cognitive outcomes by gestational age group. Values are

presented as mean [standard deviation] unless otherwise indicated.

��32 weeks ��33 weeks

Twin-to-

twin cases

Regional

cohort

Twin-to-

twin cases

Regional

cohort

n 24 814 20 291

IQ score 89 [16] 102 [11] 102 [9] 105 [11]

IQ difference

(95% CI)

13 (9 to 18) 3 (�2 to 8)

P 0.0001 0.515

Table 5. Behavioural outcomes. Values are presented as median (interquartile range).

Twin-to-twin cases Comparison groups

Regional cohort Matched controls

Singletons Twins

CBCL

n 43a 26b 1191 43 26

Externalising 43 (39, 53) 44 (38, 53) 47 (40, 55) 51 (41, 57) 50 (41, 62)

Externalising difference 2 (�1, 6) 3 (�3, 8) 1 (�7, 8)

P 0.222 0.352 0.834

Total 44 (38, 53) 45 (37, 54) 49 (43, 57) 49 (41, 58) 52 (37, 60)

Total difference 3 (�1, 6) 3 (�3, 9) 1 (�6, 7)

P 0.216 0.312 0.816

VABS

n 43 27 1045 43 27

Communication 100 (90, 107) 93 (53, 124) 96 (83, 106) 95 (80, 106) 91 (66, 107)

Communication difference �4 (�23, 12) 0 (�42, 23)

P# 0.803 0.135 0.252

Daily living skills 89 (77, 98) 95 (75, 118) 84 (72, 92) 81 (75, 90) 88 (81, 96)

Daily living skills difference �6 (�1, 5) 3 (�2, 19)

P# 0.421 0.096 0.686

Socialisation 93 (84, 100) 97 (75, 123) 94 (86, 100) 94 (89, 101) 94 (85, 101)

Socialisation difference 1 (�9, 15) 0 (�8, 19)

P# 0.876 0.810 0.804

CBCL ¼ Child Behavior Check List Standardised scores; VABS ¼ Vineland Adaptive Behavior Scales Standardised scores.a Twin-to-twin transfusion subset matched with singleton controls.b Twin-to-twin transfusion subset matched with twin controls.# P value determined from Wilcoxon two-sample test (regional cohort) and Wilcoxon matched pairs signed ranks test (matched controls).



stage 1 at diagnosis, with the cerebral palsy single surviving

twin being stage 3 at diagnosis (the donor with absent end

diastolic flow in the umbilical artery).

DISCUSSION

This is the first study to report a broad spectrum of long

term outcomes in childhood survivors of twin-to-twin

transfusion syndrome. It is also the first to contrast these

outcomes in a rigorous manner with a contemporaneous

regional comparison group. Children born very preterm in

the twin-to-twin transfusion syndrome group had signifi-

cantly lower IQ scores than non-twin-to-twin transfusion

syndrome twins or singletons who were also born very

preterm. There were no differences in children born at more

mature gestational ages and no differences in overall behav-

iour scores or in adaptive behaviour scores at any gestational

age. There was no increase in the prevalence of cerebral

palsy in twin-to-twin transfusion syndrome children.

Previous studies of long term childhood outcome have

reported variable rates for cerebral palsy (4.7–18%)8–12

but have not had a comparison group to ascertain if their

reported rate is higher than expected at equivalent gesta-

tional ages in their own community. Our results show a

trend to higher cerebral palsy rates in twin-to-twin trans-

fusion syndrome children and non-twin-to-twin transfusion

syndrome twins than in singletons at similar gestations.

This would be consistent with other evidence showing

higher rates in twin pregnancies.22,23 To demonstrate a

statistically significant increase in cerebral palsy in twin-

to-twin transfusion syndrome children compared with other

twins would require a very large population of twin-to-twin

transfusion syndrome children. It is likely that this would

only be available in national registries of twin-to-twin

transfusion syndrome pregnancies.

Assessments of developmental or cognitive outcome

have previously been based on use of the Griffith’s test8–11

with no formal assessment of intelligence and no appro-

priate comparison group. Thus, most of these studies have

concluded that childhood survivors of twin-to-twin trans-

fusion syndrome have a high rate of adverse long term

outcomes. They have however been unable to assess

whether this is due to their early gestational age at delivery

or is a function of the pathological process involved in

twin-to-twin transfusion syndrome and is hence an addi-

tional risk in these survivors. Our study would suggest that

there are additional risks to development from being a

member of a twin-to-twin transfusion syndrome pregnancy,

particularly with the decrement in IQ score that we have

observed in those born at very preterm gestations. Com-

bining a cohort comparison and a case–control cohort

makes us confident that we are describing a true difference

in IQ scores. The estimate of this IQ difference would

indicate that it would be of practical significance in these

children in later life.

Necrosis of cerebral white matter has been described in

preterm monochorionic twins and is related to vascular

connections between their placental circulations.24 It was

more common in those infants with functioning placental

intravascular anastomoses. The infants in that study were

all less than 36 weeks of gestational age but no breakdown

of gestation by white matter lesion was given. This may be

the underlying pathological process that leads to the ad-

verse cognitive outcome in our very preterm infants. Thus,

our results would suggest that, although the insult is

antenatal, delivery at a very preterm gestation makes the

brain more susceptible to damage.

The occurrence of a single intrauterine death in mono-

chorionic twin pregnancies has been associated with a risk

of neurologic sequelae in the survivor of 17–46.2%.25–27

Bajoria et al.28 reported the risk of adverse sequelae in twin-

to-twin transfusion syndrome pregnancies to be related to

which twin died first. Intrauterine demise of the recipient

was associated with an increased frequency of subsequent

co-twin death, severe anaemia and intracranial lesions,

while demise of the donor was associated with a normal

outcome in the recipient. Mari et al.12 did not observe this

phenomenon with only one of three recipient survivors

assessed as neurologically normal. One of our five single

surviving assessed twins has neurologic handicap and it is

likely that the placental vascular anastomoses and second-

ary haemodynamic alterations following single demise con-

tribute to these outcomes, independent of fetal recipient/

donor status.

There were no differences in behavioural scores between

twin-to-twin transfusion syndrome children and the com-

parison group either in the multivariate analysis or in the

case–control analysis. This is the first report of behavioural

outcomes in twin-to-twin transfusion syndrome children

and is important, as it suggests no increase in behaviours

that might relate to later problems with attention or hyper-

activity. The scores on the VABS also suggest that these

children function appropriately in their home environment.

This positive finding however relates only to the early years

of life as few of these children have reached school age. It

will be important that they are reviewed later to examine

for deleterious effects on learning and performance at

school.

We found no differences between donor and recipients

in cognitive or behavioural outcomes and this is consistent

with results in the published literature.10,11 Similarly, we

found no relationship with twin-to-twin transfusion syn-

drome stage for any outcome.

CONCLUSION

Most of the children from this cohort of twin-to-twin

transfusion syndrome pregnancies are functioning within

the normal range on their cognitive and behavioural assess-

ments. Of the seven children with disability, three were

CHILDHOOD OUTCOMES IN TWIN-TO-TWIN TRANSFUSION SYNDROME 67


considered to have severe disability based on IQ, with one of

these children also having mild cerebral palsy. This is de-

spite the major adverse events they have experienced ante-

natally and perinatally. This knowledge is critical to parents

when they are being counselled and advised at the time of

their initial presentation during pregnancy with twin-to-twin

transfusion syndrome.

Acknowledgements

This study was supported by a research grant from the

Women and Infants Research Foundation, Perth, Western

Australia.

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Accepted 11 May 2004



the long term neurologic outcome of children from pregnancies complicated by twin-to-twin...

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