The primary outcome is the composite outcome termed NDI, which is defined as the presence of at least one of the following: abnormal neurological outcome (cerebral palsy), cognitive or psychomotor development score < 2 SD, bilateral blindness, and bilateral deafness requiring amplification. The following potential predictors for NDI will be studied in a univariate logistic regression model: praematurity, severity of fetal anaemia, presence and severity of fetal hydrops, number of IUT procedures, severe neonatal morbidity (including respiratory distress syndrome, intraventricular haemorrhage ≥ grade 3[
17], periventricular leukomalacia ≥ grade 2[
18], necrotising enterocolitis ≥ grade 2[
15] and/or sepsis) and perinatal asphyxia. Multivariable logistic regression model will be used to measure the independent effects of potential predicting factors on outcome.
Neurological outcome
In this study the neurological outcome is assessed in all children by a single pediatrician by performing a neurological examination according to Touwen [
19] and scored as normal, minor neurological dysfunction, or abnormal. A minor neurological dysfunction is defined as a moderate abnormality of tone, posture, and movement leading to only minor functional impairment or a minor developmental delay. Abnormal development is defined as severe abnormality of tone, posture, and movement leading to functional impairment and/or a delay in motor development. Presence of cerebral palsy (CP) is assessed according to the criteria of the European CP Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic or mixed [
20].
Cognitive and psychomotor development
Cognitive and psychomotor development of children aged 2 to 3 years is assessed according to the Dutch version of the Bayley Scales of Infant Development, 2
nd edition (BSID-II)[
21]. BSID-II scores provide a mental developmental index (MDI) and a psychomotor developmental index (PDI). The MDI and PDI follow a normal distribution curve with a mean score of 100 and a standard deviation of 15. Scores are classified into one of three categories: normal limits (standard scores of ≥ 85); mildly delayed (standard scores of 70-84); and significantly delayed (standard scores of ≤ 70).
Children between 3 and 7 years of age are tested with the Dutch version of the Wechsler Preschool Performance Scale of Intelligence, 3
rd edition (WPPSI-III-NL) [
22]. Cognitive development in children between 7 and 16 years of age is assessed with the Dutch version of the Wechsler Intelligence Scale for Children, 3
rd edition (WISC-III-NL) [
23]. Both tests provide a full scale IQ score, a Verbal IQ and a Performance IQ. Scores have a mean of 100 and a SD of 15. Scores of <70 are classified as extremely low, 70 to 79 as borderline, 80 to 89 as low average, 90 to 110 as average, 111 to 119 as high average, 121 to 130 as superior, and ≥ 130 as very superior. All tests are performed by a licensed psychologist.
Psychosocial functioning and Health related Quality of life
Psychosocial follow-up is assessed in children between 4 years to 16 years of age using the Dutch version of the Strengths and Difficulties Questionnaire (SDQ) [
24]. The SDQ is available as an informant-rated version for children aged 4 years and older (to be completed by parents, teachers or caregivers). The SDQ assesses mental and behavioural difficulties and strengths along the following dimensions: emotional symptoms, conduct problems, hyperactivity/inattention, peer problems and prosocial behaviour. Each scale consists of 5 items, each rated on a 3-point scale (not true, somewhat true and certainly true). Higher scores indicate more problems on the respective difficulties dimension or less appropriate behaviour for the prosocial scale. In addition to dimension-specific scores, the first 4 scales can be summed up to a total difficulties score, with higher scores indicating more problems.
Health related Quality of Life (HRQoL) is assessed in children between 6 years and 22 years of age using the TNO AZL Child Quality Of Life (TACQOL) [
25] and the TNO Adult Quality of Life (TAAQOL)[
26]. The TACQOL child- and parent form cover 7 eight-item domains of life: physical complaints, motor functioning, autonomy, cognitive functioning, social functioning, positive emotions and negative emotions. The TACQOL assesses the frequency of difficulties experienced in 'the last few weeks' with response categories: never, occasionally or often. If a difficulty is experienced occasionally or often, the emotional reaction to this problem is determined. Items are scored by assigning a value of 4 to the 'never' response, a value of 3 to a 'feeling fine' response, a value of 2 to a 'feeling not so good response, a value of 1 to a 'feeling quite bad' response and a value of 0 to a 'feeling bad' response. The scores in each domain range from 0 to 32. The scales for positive and negative emotions, asking for the frequency of moods on a 3-pointscale (score 0 'never', score 1 'occasionally', score 2 'often'), range from 0 to 16. In all seven domains higher scores indicate better HRQoL.
The TAAQOL covers 12 domains: gross motor functioning, fine motor functioning, pain, sleeping, cognitive functioning, social functioning, daily activities, sexual activity, vitality, happiness, depressive moods, and aggressiveness. First the frequency of occurrence of a specific complaint or limitation during the last month is asked. If such a problem has occurred, the subjective appraisal of this problem is assessed. A score of 1 is given when there is no limitation, a score of 2 when there is a limitation ('a little', 'some' or 'a lot') but when the person is not bothered by this limitation; a score of 3 when there is a limitation and the person experiences this limitation 'a little' negatively; a score of 4 when there is a limitation and the person experiences this limitation 'quite a lot' negatively; and a score of 5 when there is a limitation and the person experiences this limitation 'very much' negatively. Scores of each subscale are normalised to a scale ranging from 0 to 100, with higher scores indicating better HRQoL.
Life-achievement forms based on the POPS-19 study are obtained in children between 8 and 22 years of age. All tests and questionnaires for the parents and children are summarised in table
1.
Table 1
An overview of child and proxy questionnaires and tests for paediatric neuromotor, cognitive and psychosocial development in all children treated with IUT for alloimmune fetal anaemia.
2 | | | | BSID-III-NL |
3 | | | | |
4 | | | | |
5 | | | Proxy questionnaire | WPPSI-III-NL |
6 | | | | |
7 | | | | |
8 | | | | |
9 | | | | |
10 | | | | |
11 | | | | |
12 | TACQOL | SDQ/ | | |
13 | | TACQOL | | |
14 | | | | |
15 | | | | |
16 | | | | WISC-III-NL |
17 | | | Child questionnaire | |
18 | | | | |
19 | | | | |
20 | TAAQOL | | | |
21 | | | | |
22 | | | | |