Objective
This study was performed to report the neurodevelopmental outcome of survivors of twin-twin transfusion syndrome (TTTS) treated with laser surgery and to determine the risk factors for neurodevelopmental disability.
Study Design
A prospective study of TTTS cases treated with laser was performed. Survivors were assessed at 2 years corrected for prematurity. Neurodevelopmental disability was defined as the presence of cerebral palsy, deafness, blindness, or cognitive impairment with a developmental score >2 SDs below the mean.
Results
A total of 75 TTTS pregnancies were treated with a perinatal survival rate of 79.3%. A total of 113 survivors were assessed. The rate of cerebral palsy was 4.4% and cognitive impairment was 8%, with a neurodevelopmental disability rate of 12.4%. Quintero stage was the only independent risk factor for neurodevelopmental disability.
Conclusion
The incidence of neurodevelopmental disability in TTTS survivors treated with laser is considerable, with Quintero stage being an independent risk factor.
Twin-twin transfusion syndrome (TTTS) occurs in up to 9-15% of monochorionic pregnancies and results from unbalanced blood flow from a donor twin to a recipient twin through placental anastomoses. The donor twin develops hypovolemia and impaired renal blood flow leading to oliguria while the recipient twin develops hypervolemia and polyuria. Accordingly there is an appreciable risk for brain injury leading to neurodevelopmental disability in long-term survivors. This is especially the case when 1 twin dies in utero resulting in marked hemodynamic imbalance between the twins and subsequent brain lesions.
Serial amnioreduction as a treatment option for severe TTTS results in an improved survival compared to expectant management, but the underlying transfusion process continues with survivors having a high incidence of neurodevelopmental disability. More recently fetoscopic laser ablation surgery of placental vascular anastomoses has been advocated as the preferred treatment with a metaanalysis concluding that laser surgery compared to amnioreduction was significantly associated with perinatal survival with an odds ratio (OR) of 2.04 (95% confidence interval [CI], 1.52–2.76). Furthermore the laser-treated group had a significantly lower risk for short-term neurological morbidity with an OR of 0.20 (95% CI, 0.12–0.33). Thus with laser ablation surgery for TTTS, as the blood flow between the fetuses is interrupted there is a potential to reduce major neurodevelopmental disability in survivors. There are few studies, however, that have documented in detail the long-term outcome of TTTS pregnancies with cerebral palsy rates ranging from 6–13.5% and neurodevelopmental disability rates ranging from 13–18% having been reported.
We have previously documented the outcomes of 100 TTTS pregnancies treated with selective fetoscopic laser ablation. The main objective of the present study was to report the neurodevelopmental outcome of a large group of survivors of severe TTTS pregnancies treated with laser surgery and to determine risk factors for major neurodevelopmental disability.
Materials and Methods
The survivors of consecutive pregnancies with TTTS treated with selective fetoscopic laser ablation surgery at the Centre for Maternal Fetal Medicine at the Mater Mothers’ Hospital, Brisbane, Queensland, Australia, from March 2002 through March 2006 were included in this study. This is the largest referral center providing intrauterine laser treatment for TTTS in Australia and New Zealand. TTTS was diagnosed by ultrasound with polyhydramnios in 1 twin sac and oligohydramnios in the co-twin of a monochorionic twin pregnancy with the pregnancies being staged prospectively according to the criteria of Quintero et al. Fetoscopic laser surgery was performed as previously described for stage II-IV TTTS cases. A total of 36 (48%) of 75 mothers resided in Queensland with the remainder being referred from other centers in Australia and New Zealand. In 1 case insertion of the fetoscope was followed by a persistent fetal bradycardia and laser surgery was not performed. This pregnancy was subsequently managed by amnioreduction but has been included in the analysis on an intention-to-treat basis. In no case was a second laser procedure undertaken. Additionally, no case of persistent or reverse fetofetal transfusion was identified, nor any case in which an intrauterine blood transfusion was required for severe anemia in either twin. Data recorded included: gestational age at the time of laser surgery, Quintero stage of TTTS and uterine site of the placenta, intrauterine fetal death, gestational age at delivery, small for gestational age (SGA), gender of the twins, neonatal death (defined as death prior to hospital discharge), and infant death. SGA was defined as a birthweight <10th centile for twins.
The survivors were assessed at the age of at least 2 years corrected for prematurity. The assessment included a physical and neurological examination performed by a pediatrician with cerebral palsy being diagnosed according to the criteria of Mutch et al. Children with cerebral palsy were classified further according to severity using the Gross Motor Functional Classification Scale (GMFCS). An assessment of cognitive function was performed by experienced pediatric psychologists. The majority of the children were assessed using the Griffiths Mental Development Scales (general quotient [GQ], mean 100, SD 12). Some children were assessed by psychologists without access to the Griffiths Scales, and hence they were assessed using either the Bayley Scales of Infant Development, Second Edition (BSID-II) (mean, 100; SD, 15), or the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) (mean, 100; SD, 15). Cognitive impairment was diagnosed with a score of >2 SDs below the mean: Griffiths GQ <76, BSID-II, mental development index <70, Bayley-III, cognitive score <70. Formal audiological assessment and ophthalmological reviews were performed as clinically indicated.
Neurodevelopmental disability was diagnosed on the basis of the presence of cerebral palsy, cognitive impairment, bilateral blindness, or deafness requiring amplification with hearing aids.
The study was approved by Mater Health Services Human Research and Ethics Committee. All parents gave informed consent.
Statistical analyses
Data are presented as mean and SD for normally distributed continuous variables and median and range for nonparametric distributions. Continuous variables were tested for normality using the Shapiro-Wilk test with the results verified by examining Q-Q plots. Univariate analysis with a random twin effect was applied to adjust for the possible effect within twin pairs, and Fisher’s exact test was used where 0 cells were encountered. Predictors for neurodevelopmental disability that had a significance value < .10 or were found in previous studies to be statistically significant were included in a multivariate logistic regression model to measure independent effects. The birthweight predictor was analyzed in 100-g intervals. The results were expressed as OR and 95% CI. Statistical significance was considered to be present at the .05 level. Analyses were performed using software (StataSE 9.2; StataCorp LP, College Station, TX).
Results
Seventy-five mothers with TTTS pregnancies were treated during the study period. Analysis according to Quintero stage revealed stage II in 19 cases (25%), stage III in 37 cases (49%), and stage IV in 19 cases (25%). The mean (SD) gestational age at laser was 21.5 (2.7) weeks (range, 17–28 weeks). Three procedures were performed >26 weeks. The mean (SD) gestational age at delivery was 31 (4.2) weeks (range, 20–38 weeks). The mean (SD) gestational age for live-born infants was 31.7 (3.5) weeks (range, 22–38 weeks). The fetal death in utero rate was 14% (21/150) with a neonatal death rate of 6.7% (10/150). The overall perinatal survival rate was 79.3% (119/150). The mean (SD) gestational age for neonatal survivors was 32.2 (3.0) weeks (range, 25–38 weeks). Survival to hospital discharge by Quintero stage was 74%, 76%, and 92% for stages II, III, and IV, respectively ( P = .06). Three children died after hospital discharge, 1 of respiratory infection aged 8 months and a set of twins of sudden infant death syndrome at the age of 4 months. Three children were lost to follow-up. Twins born at 34 weeks of gestation who had normal cranial ultrasound scan results were lost to follow-up after the 1-year visit when they had normal GQs on the Griffiths Scales and with no evidence of cerebral palsy. The third child was born at 30 weeks of gestation (co-twin, intrauterine fetal death) and had normal cranial ultrasound scan findings. While contact was made at 2 years with the family, they declined to bring the child for assessment but provided information that the child was developing normally. These 3 children were excluded from the analysis.
Accordingly neurodevelopmental data were available for 113 (97%) long-term survivors. The perinatal characteristics of these infants are shown in Table 1 . Follow-up at the Mater Mothers’ Hospital occurred for 55 (49%) children with the remainder being assessed at the centers of referral. The median age corrected for prematurity for follow-up was 110 weeks (interquartile range, 104–130 weeks; range, 93–199 weeks). For assessment of cognitive function 81 (72%) children had the Griffiths Scales, 15 (13%) had the BSID-II, and 17 (15%) had the Bayley-III.
