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Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syndrome

      Objective

      We sought to assess long-term neurodevelopment of children who were treated prenatally as part of the Eurofoetus randomized controlled trial.

      Study Design

      The study population was composed of 128 cases of twin-to-twin transfusion syndrome (TTTS) included and followed up in France. Survivors were evaluated by standardized neurological examination and by Ages and Stages Questionnaires (ASQ). Primary outcome was a composite of death and major neurological impairment.

      Results

      A total of 120 children (47%) were alive at the age of 6 months and were followed up to the age of 6 years. At the time of diagnosis, only treatment and Quintero stage were predictors of a poor outcome (hazard ratio, 0.61; 95% confidence interval, 0.41–0.90; P = .01 and hazard ratio, 3.23; 95% confidence interval, 2.19–4.76; P < .001, respectively). Children treated by fetoscopic selective laser coagulation (FSLC) had higher ASQ scores at the end of follow-up (P = .04).

      Conclusion

      FSLC was significantly associated with a reduction of the risk of death or long-term major neurological impairment at the time of diagnosis and treatment.

      Key words

      Twin-to-twin transfusion syndrome (TTTS) develops in 10-20% of monochorionic diamniotic pregnancies
      • Graef C.
      • Ellenrieder B.
      • Hecher K.
      • Hackeloer B.J.
      • Huber A.
      • Bartmann P.
      Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      with a mortality rate of approximately 90% for both twins if untreated.
      • Saunders N.J.
      • Snijders R.J.
      • Nicolaides K.H.
      Therapeutic amniocentesis in twin-twin transfusion syndrome appearing in the second trimester of pregnancy.
      Survivors are exposed to subsequent neurological handicap, either as a result of preterm birth or of the disease itself.
      • Hecher K.
      • Plath H.
      • Bregenzer T.
      • Hansmann M.
      • Hackeloer B.J.
      Endoscopic laser surgery versus serial amniocenteses in the treatment of severe twin-twin transfusion syndrome.
      For Editors' Commentary, see Table of Contents
      In a recent randomized trial, the Eurofoetus trial,
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      we found that fetoscopic selective laser coagulation (FSLC) of the chorionic vessels is a more effective first-line treatment than serial amniodrainage (AD) in severe TTTS diagnosed before 26 weeks of gestation. FSLC offers a treatment option that is based on the pathophysiology of the disease and interrupt placental anastomoses, resulting in a higher survival rate and fewer neurological sequelae in survivors at 6 months of age.
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      However, uncertainty about long-term neurological outcome remains a major concern for both parents and physicians.
      • Stamilio D.M.
      • Fraser W.D.
      • Moore T.R.
      Twin-twin transfusion syndrome: an ethics-based and evidence-based argument for clinical research.
      • Wagner M.M.
      • Lopriore E.
      • Klumper F.J.
      • Oepkes D.
      • Vandenbussche F.P.
      • Middeldorp J.M.
      Short- and long-term outcome in stage 1 twin-to-twin transfusion syndrome treated with laser surgery compared with conservative management.
      Cognitive and motor developmental delay are relatively common and have been related to both FSLC and AD.
      • Graef C.
      • Ellenrieder B.
      • Hecher K.
      • Hackeloer B.J.
      • Huber A.
      • Bartmann P.
      Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      • Banek C.S.
      • Hecher K.
      • Hackeloer B.J.
      • Bartmann P.
      Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      • Lopriore E.
      • Middeldorp J.M.
      • Sueters M.
      • Oepkes D.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      • Lopriore E.
      • Nagel H.T.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome.
      • Lopriore E.
      • Ortibus E.
      • Acosta-Rojas R.
      • et al.
      Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.
      • Sutcliffe A.G.
      • Sebire N.J.
      • Pigott A.J.
      • Taylor B.
      • Edwards P.R.
      • Nicolaides K.H.
      Outcome for children born after in utero laser ablation therapy for severe twin-to-twin transfusion syndrome.
      • Wadhawan R.
      • Oh W.
      • Perritt R.L.
      • et al.
      Twin gestation and neurodevelopmental outcome in extremely low birth weight infants.
      Therefore, we prospectively studied the neurologic and neurodevelopmental outcomes up to the age of 6 years in infants included in the Eurofoetus randomized controlled trial (RCT) in years 1999-2002.

      Materials and Methods

      Design and study protocol

      We studied the long-term follow-up of TTTS cases included in a RCT, the Eurofetus RCT.
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      The initial study was a multicentric, randomized, and stratified by country, AD vs FSLC controlled trial of 142 women with monochorionic twins and TTTS recruited in 6 countries. Of the total population, 90% (128 cases) were recruited in France.
      The trial was conducted between January 1999 and March 2002.
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      Briefly, women presenting between 15 and 26 weeks of gestation with severe TTTS were invited to participate and were randomly allocated to laser surgery (FSLC group) or serial amniodrainage (AD group). The Quintero system was used to stage the disease.
      • Quintero R.A.
      • Morales W.J.
      • Allen M.H.
      • Bornick P.W.
      • Johnson P.K.
      • Kruger M.
      Staging of twin-twin transfusion syndrome.
      Exclusion criteria were fetal death, major fetal anomaly, ruptured membranes, maternal conditions requiring delivery, and any previous invasive therapy directed at the syndrome.
      Following treatment, the decision to deliver was based on obstetrical indications and was made by the attending perinatologist; however, all deliveries were performed no later than 37 completed weeks of gestation. Placentas were assessed after delivery to confirm chorionicity.
      The protocol was approved by the institutional review board at each center. Perinatal and infant data were provided by the treating clinicians, and outcomes up to the age of 6 months were assigned by only 1 neonatologist who had no knowledge of the assigned treatment. We prospectively followed up the 128 cases that were delivered in France for neurological and neurodevelopmental evaluation up to 6 years of age.

      Outcome variables

      Primary outcome was a composite of pre/postnatal death and major neurological impairment (see the following text) at follow-up. In addition, survivors were subjected to neurological and neurodevelopmental follow-up up to 6 years of age.

      Neurological follow-up

      The children were followed up by questionnaires sent to the treating clinicians caring for patients to assess physical status as well as their neurologic development. These questionnaires were to be answered at the age of 1 and 2 years.
      All children underwent the standardized physical and neurological examination developed by Amiel-Tison and Gosselin
      • Amiel-Tison C.
      • Gosselin J.
      Démarche clinique en neurologie du développement.
      and Deschenes and colleagues
      • Deschenes G.
      • Gosselin J.
      • Couture M.
      • Lachance C.
      Interobserver reliability of the Amiel-Tison neurological assessment at term.
      at the age of 5 years. These consisted of a detailed neurological examination that explores the neurological status. A single investigator, blinded to the mode of treatment, examined all but 10 children. The treating pediatrician or general practitioner examined these 10 children living too far away from a hospital or whom parents declined follow-up.
      The children were classified into 3 groups according to follow-up data. Cerebral palsy was defined clinically and classified according to the European Cerebral Palsy Network recommendations.
      • Christine C.
      • Dolk H.
      • Platt M.J.
      • Colver A.
      • Prasauskiene A.
      • Krageloh-Mann I.
      Recommendations from the SCPE collaborative group for defining and classifying cerebral palsy.
      According to the neurological questionnaires and examination, development was classified as no neurological impairment (N1, normal physical and neurological examination results), minor impairment (N2, neurological deficiencies with prospect to normalization, including strabismus, mildly retarded motor and speech development), or major neurological impairment (N3, cerebral palsy with neurological abnormalities including hemiparesis, spastic quadriplegia, and blindness).
      The parents also received Ages and Stages Questionnaires (ASQ) at 12, 24, 48, and 60 months.
      • Squires J.
      • Bricker D.
      • Potter L.
      Revision of a parent-completed development screening tool: Ages and Stages Questionnaires.
      The ASQ is a parent-completed child-monitoring system that has been validated against the Bayley Scales of Infant Development as a screening tool for abnormal development.
      • Squires J.
      • Bricker D.
      • Potter L.
      Revision of a parent-completed development screening tool: Ages and Stages Questionnaires.
      It contains 5 domains of child development (communication, gross motor skills, fine motor skills, problem-solving skills, and personal social skills). Each domain consists of 6 questions about what the child can or cannot do. The answer to each question is “yes,” “sometimes,” or “not yet” and is graded with 10, 5, or 0 points, respectively. Domain scores are then obtained by the sum of the items and compared with established screening cutoff points according to ASQ guidelines. This evaluation tool has been used extensively and has a high sensitivity and specificity to detect children with developmental delays.
      • Squires J.
      • Bricker D.
      • Potter L.
      Revision of a parent-completed development screening tool: Ages and Stages Questionnaires.
      American Academy of Pediatrics CoCwD
      Developmental surveillance and screening of infants and young children.
      • Dionne C.
      • Squires J.
      • Leclerc D.
      Psychometric properties of a developmental screening test: using the Ages and Stages Questionnaires (ASQ) in Quebec and the US.
      • Skellern C.Y.
      • Rogers Y.
      • O'Callaghan M.J.
      A parent-completed developmental questionnaire: follow up of ex-premature infants.
      All children were assessed with these questionnaires.

      Neurodevelopmental follow-up

      At the age of 6 years, the Wechsler Intelligence Scale for Children (WISC-IV) was used to evaluate the children's psychological development.
      • Gregoire J.
      L'examen clinique de l'intelligence de l'enfant.

      Weschler D. WISC-IV. Echelle d'intelligence de Weschler pour enfants. Quatrième édition. In: ECPA, ed. Paris; 2005.

      This is a clinical instrument administered for the evaluation of intelligence in children between 6 and 16 years. The WISC-IV addresses the intellectual functioning in specific cognitive domains (verbal comprehension [VC], perceptive reasoning [PR], work memory [WM], processing speed [PS]). The WISC-IV score also provides evaluation of the general intellectual capacity of the child through a composite score of total scale, the intelligence quotient (IQ).
      The Goodenough Draw-a-Man test
      • Goodenough F.
      A new approach to the measurement of intelligence of young children.
      • Tramill J.L.
      • Edwards R.P.
      • Tramill J.K.
      Comparison of the Goodenough-Harris Drawing Test and the WISC-R for children experiencing academic difficulties.
      • Naglieri J.A.
      • Maxwell S.
      Inter-rater reliability and concurrent validity of the Goodenough-Harris and McCarthy Draw-A-Child scoring systems.
      • Bjerre I.
      Neurological investigation of 5-year-old children with low birthweight.
      was also used to determine the mental age of the child according to its graphic capabilities with reference to the elements recorded on or absent from the drawing. A psychologist, blinded to the mode of treatment, specifically trained to use this method did perform this psychological evaluations in all children.

      Statistical methods

      Long-term survival and neurological and neurodevelopmental outcomes were studied in relation to treatment group and other potential predictors such as status of donor or recipient, gestational age (GA) at treatment (truncated at median value below or above 160 days), and Quintero stage (3 or 4 vs 1 or 2). Uni- and multivariate survival analyses were performed to identify predictors of death and of neurological impairment (N3). The relationship with outcome of infants was estimated by survival analysis, taking into account the inherent interdependence between twins by a gamma frailty Cox model.
      • Rondeau V.
      • Gonzalez J.R.
      Frailtypack: a computer program for the analysis of correlated failure time data using penalized likelihood estimation.
      For a composite outcome (death or major neurological impairment), cumulative incidence was described by Kaplan-Meier curves. All tests were 2 tailed and P values of less than .05 were considered significant. Analysis was performed with the use of R statistical language (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org).

      Results

      The population initially studied included 68 women (136 fetuses) treated in the FSLC and 60 women (120 fetuses) in the AD group, respectively. The median [interquartile range] maternal age was 32 [29–36] years in both groups, GA at diagnosis was 21 [19–22.8] and 20.6 [19–22.7] weeks in the FSLC and the AD group, respectively (P = .79). There were 24 (35%) and 18 (30%) of nulliparous in the FSLC and the AD group, respectively (P = .5).
      In the FSLC group, 37% (n = 50) and 9% (n = 13) of fetuses died in utero and in the neonatal period, respectively. In the AD group, there were 39% (n = 47) and 22% (n = 26) died in utero and in the neonatal period, respectively. Seventy-three (54%) (22 pairs, 16 recipients, and 13 donors) and 47 fetuses (39%) (16 pairs, 4 recipients, and 11 donors) were born alive and were alive at 6 months of age in the FSLC and AD groups, respectively (Figure 1). As described in the initial study, the survival rate at 6 months was significantly higher in the FSLC group than the AD group (P = .01).
      Figure thumbnail gr1
      FIGURE 1Flowchart of patients from the Eurofetus randomized controlled trial
      D, donor; R, recipient.
      Salomon. Long-term neurological outcome in TTTS. Am J Obstet Gynecol 2010.
      There were no additional deaths up to the end of follow-up of the 120 infants who were alive at the age of 6 months. Neurological follow-up of twins up to the age of 6 years was available for all infants but 4 and 6 in the FSLC and AD groups, respectively (lost to follow-up rate was 10 of 120 [8%], of whom 5 were followed up until the age of 2 years). At the end of follow-up, 60 (82%) and 33 (70%) of the children had a normal neurological evaluation in the FSLC and AD treatment groups, respectively (P = .12). The detailed incidence of neurological impairment for each group is presented in Table 1.
      TABLE 1Neurologic follow-up at 6 years
      VariableFSLC (n = 73)AD (n = 47)
      DonorRecipientTotalDonorRecipientTotal
      N1322860 (82%)211233 (70%)
      N2000 (0%)022 (4%)
      N3369 (12%)246 (13%)
      N2 plus N3, n (%)9 (12)8 (17)
      Neurologic impairment, n
       Cerebral palsy369246
       Blindness022011
       Deafness011101
      Cerebral palsy classification, n
       Mono/hemiplegia224112
       Diplegia000011
       Quadriplegia145123
      Lost to follow-up044 (5%)336 (13%)
      N1 is no neurological impairment (normal physical and neurological examination results); N2 is minor abnormalities (neurological deficiencies with prospect to normalization, including strabismus, mildly retarded motor and speech development); N3 is major impairment (cerebral palsy with neurologic abnormalities including hemiparesis, spastic quadriplegia, and blindness).
      AD, amniodrainage; FSLC, fetoscopic selective laser coagulation.
      Salomon. Long-term neurological outcome in TTTS. Am J Obstet Gynecol 2010.
      At the time of randomization, both Quintero stage (P < .001) and treatment group (P = .01) were significant predictors of death or severe neurological outcome. In the multivariate analysis, treatment and Quintero stage at diagnosis remained significant predictors of a poor outcome (hazard ratio, 0.61; 95% confidence interval, 0.41–0.90; P = .01 and hazard ratio, 3.23; 95% confidence interval, 2.19–4.76; P < .001, respectively). Results of both univariate and multivariate analysis are shown in Table 2.
      TABLE 2Uni- and multivariate analysis of potential prenatal predictors of death or major neurologic impairment (N3)
      VariableUnivariate analysisMultivariate analysis
      βSEP valueβSEP value
      Treatment group (FSLC vs AD)−0.7240.315.022
      Statistically significant difference.
      −0.4980.202.014
      Statistically significant difference.
      Quintero stage (3 or 4 vs 1 or 2)2.0100.298<10−5
      Statistically significant difference.
      1.1730.198<10−5
      Statistically significant difference.
      Twin type (recipient vs donor)0.1110.174.500
      GA at treatment (>160 d vs <160 d)−0.0220.330.950
      AD, amniodrainage; FSLC, fetoscopic selective laser coagulation; GA, gestational age.
      Salomon. Long-term neurological outcome in TTTS. Am J Obstet Gynecol 2010.
      a Statistically significant difference.
      Figure 2 illustrates survival with no major neurological impairment in the 2 groups. ASQ scores were evaluated in all but 17 (14%), 18 (15 %), and 28 (23%) infants at the age of 24, 48, and 60 months, respectively. Although they were comparable at up to 48 months, those infants treated in the laser group had higher ASQ scores at the age of 5 (60 months): 261.3 ± 53.7 vs 228.6 ± 79.1; P = .04. Table 3 provides detailed results of the neurological evaluation in both groups.
      Figure thumbnail gr2
      FIGURE 2Probability of survival with no major neurological impairment
      After adjustment for Quintero stage, treatment remained a significant predictor of poor outcome (hazard ratio, 0.61; 95% confidence interval, 0.41–0.90; P = .01).
      Salomon. Long-term neurological outcome in TTTS. Am J Obstet Gynecol 2010.
      TABLE 3Results of the ASQ evaluation, WISC-IV, and Draw-a-Man test
      FSLCn (%) missing dataADn (%) missing dataP value
      ASQAt 24 moCommunication42.4 ± 21.47 (10)36.25 ± 20.010 (21)
      Global motor skills42.7 ± 17.539.9 ± 19.5
      Fine motor skills40.2 ± 17.343.0 ± 18.1
      Problem solving skills38.5 ± 16.134.5 ± 15.3
      Personal social score40.2 ± 15.638.3 ± 15.9
      Raw total score203.3 ± 79.6191.9 ± 76.4.3
      At 48 moCommunication50.6 ± 13.08 (11)46.6 ± 17.610 (21)
      Global motor skills46.6 ± 15.647.4 ± 17.7
      Fine motor skills43.8 ± 16.943.1 ± 18.6
      Problem solving skills46.4 ± 17.952.0 ± 11.7
      Personal social score48.0 ± 12.743.6 ± 18.4
      Raw total score241 ± 57.6227.1 ± 80.8.8
      At 60 moCommunication52.5 ± 12.215 (21)45.3 ± 18.113 (27)
      Global motor skills53.5 ± 10.748.1 ± 18.1
      Fine motor skills50.4 ± 15.544.8 ± 20.4
      Problem solving skills52.6 ± 13.145.6 ± 18.2
      Personal social score52.1 ± 10.044.8 ± 15.8
      Raw total score261.3 ± 53.7228.6 ± 79.1.04
      Statistically significant difference.
      WISC-IV scores and total IQVC98.8 ± 21.218 (25)99.4 ± 36.619 (40)
      WM88.7 ± 20.992.3 ± 33.9
      PR93.7 ± 22.387.9 ± 31.3
      PS86 ± 17.382.4 ± 28.2
      Total IQ90.6 ± 19.991 ± 33.1.27
      Draw-a-Man test (points)11.3 ± 3.218 (25)10.7 ± 4.219 (40).9
      Results are given as mean ± SD. The WISC-IV represents the intellectual functioning in specific cognitive domains by composite notes (VC, PR, WM, PS).
      AD, amniodrainage; ASQ, Ages and Stages Questionnaires; FSLC, fetoscopic selective laser coagulation; IQ, intelligence quotient; PR, perceptive reasoning; PS, processing speed; VC, verbal comprehension; WM, work memory.
      Salomon. Long-term neurological outcome in TTTS. Am J Obstet Gynecol 2010.
      a Statistically significant difference.
      Neurodevelopmental follow-up as assessed by the WISC-IV scale and Draw-a-Man Test was comparable in both treatment groups and is also shown in Table 3.

      Comment

      In a recent randomized controlled trial, we demonstrated that, in severe TTTS cases presenting before 26 weeks, FSLC was associated with both higher survival rate and lower occurrence of neurological sequelae at 6 months of age than AD.
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      Although survival and short-term outcome is a major issue, long-term outcome remains the most important concern for both parents and physicians. The published frequency of major neurological abnormalities in survivors of TTTS after FSLC ranges between 6% and 25%.
      • Graef C.
      • Ellenrieder B.
      • Hecher K.
      • Hackeloer B.J.
      • Huber A.
      • Bartmann P.
      Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      • Banek C.S.
      • Hecher K.
      • Hackeloer B.J.
      • Bartmann P.
      Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      • Lopriore E.
      • Middeldorp J.M.
      • Sueters M.
      • Oepkes D.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      • Lopriore E.
      • Ortibus E.
      • Acosta-Rojas R.
      • et al.
      Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.
      • Sutcliffe A.G.
      • Sebire N.J.
      • Pigott A.J.
      • Taylor B.
      • Edwards P.R.
      • Nicolaides K.H.
      Outcome for children born after in utero laser ablation therapy for severe twin-to-twin transfusion syndrome.
      • Lopriore E.
      • van Wezel-Meijler G.
      • Middeldorp J.M.
      • Sueters M.
      • Vandenbussche F.P.
      • Walther F.J.
      Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      However, these findings were based on small, retrospective, uncontrolled studies.
      In the present prospective study, the overall rate of major neurological abnormalities was 12% and is consistent with those results previously published. More importantly, we have demonstrated that at the time of decision making, FSLC therapy is associated with an almost 40% reduction in the risk of fetal death or long-term major neurological impairment and that infants treated in the FSLC group had higher ASQ scores at the age of 5 years (60 months).
      Although fetoscopic laser occlusion of vascular anastomoses is being increasingly advocated as the preferred treatment for TTTS,
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      • Crombleholme T.M.
      • Shera D.
      • Lee H.
      • et al.
      A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment of severe twin-twin transfusion syndrome.
      • Hecher K.
      • Diehl W.
      • Zikulnig L.
      • Vetter M.
      • Hackeloer B.J.
      Endoscopic laser coagulation of placental anastomoses in 200 pregnancies with severe mid-trimester twin-to-twin transfusion syndrome.
      • Rossi A.C.
      • D'Addario V.
      Laser therapy and serial amnioreduction as treatment for twin-twin transfusion syndrome: a metaanalysis and review of literature.
      one might argue that FSLC could allow for the most severe cases to survive and still carry a poor prognosis. Indeed, the risk of cerebral palsy in twins is 7 times higher than in singletons,
      • Blickstein I.
      Cerebral palsy in multifoetal pregnancies.
      and this is mainly associated with monochorionicity.
      • Lopriore E.
      • van Wezel-Meijler G.
      • Middeldorp J.M.
      • Sueters M.
      • Vandenbussche F.P.
      • Walther F.J.
      Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      The pathogenesis of cerebral injury in TTTS is not clearly defined. Cerebral injury may result from antenatal injury secondary to hemodynamic and hematological imbalance and/or from postnatal injury associated with prematurity and low birthweight.
      • Lopriore E.
      • van Wezel-Meijler G.
      • Middeldorp J.M.
      • Sueters M.
      • Vandenbussche F.P.
      • Walther F.J.
      Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      In this pragmatic study, we aimed at evaluating those factors that are associated with a poor outcome at the time of treatment selection. Pregnancies complicated by TTTS treated with laser had a higher survival and a lower morbidity at 6 months of age.
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      This study shows that survival did not change thereafter. Once children reach 6 months of age, treatment itself had no major impact on long-term neurological outcome. This might be explained by the fact that children with the most serious perinatal complications did not survive either spontaneously or after discharge from intensive care when diagnosed with severe brain lesions in very preterm neonates.
      • Senat M.V.
      • Deprest J.
      • Boulvain M.
      • Paupe A.
      • Winer N.
      • Ville Y.
      Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome.
      This study provides both neurological and neurodevelopmental follow-up in a large cohort of infants treated for TTTS prenatally. Importantly, we were able to keep the lost to follow-up rate below 10% for neurological long-term outcome despite the size and the origin of the cohort.
      In addition to the fact that FSLC treatment is associated with a better outcome, we also confirmed an independent association between a higher Quintero stage and neurological impairment.
      • Lopriore E.
      • Middeldorp J.M.
      • Sueters M.
      • Oepkes D.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      • Lopriore E.
      • Nagel H.T.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome.
      • Lopriore E.
      • Ortibus E.
      • Acosta-Rojas R.
      • et al.
      Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.
      This suggests that increasing severity of the disease (ie, higher Quintero stage) may lead to not only increased perinatal mortality but also increased long-term morbidity.
      • Lopriore E.
      • Nagel H.T.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome.
      • Lopriore E.
      • Ortibus E.
      • Acosta-Rojas R.
      • et al.
      Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.
      • Taylor M.J.
      • Shalev E.
      • Tanawattanacharoen S.
      • et al.
      Ultrasound-guided umbilical cord occlusion using bipolar diathermy for stage III/IV twin-twin transfusion syndrome.
      We did not find any difference in neurological impairment between donor and recipient twins, suggesting that both are at equal risk in respect to adverse neurodevelopment outcome.
      These results are in agreement with previous studies.
      • Graef C.
      • Ellenrieder B.
      • Hecher K.
      • Hackeloer B.J.
      • Huber A.
      • Bartmann P.
      Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      • Banek C.S.
      • Hecher K.
      • Hackeloer B.J.
      • Bartmann P.
      Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin-twin transfusion syndrome.
      • Lopriore E.
      • Middeldorp J.M.
      • Sueters M.
      • Oepkes D.
      • Vandenbussche F.P.
      • Walther F.J.
      Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery.
      We could not confirm any relationship between advanced gestational age at therapy and impaired neurodevelopment,
      • Lopriore E.
      • Ortibus E.
      • Acosta-Rojas R.
      • et al.
      Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.
      once adjusted on other factors such as Quintero stage. As suggested by Lopriore et al,
      • Lopriore E.
      • Ortibus E.
      • Acosta-Rojas R.
      • et al.
      Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.
      we believe that this association might be explained by the small but positive correlation between gestational age at therapy and Quintero stage.
      There are some limitations of our study. Most infants in the present study were treated prenatally in the same center, and they were evaluated postnatally by the same pediatrician and by the same psychologist. One could therefore argue that our results need to be reproduced in different settings, although this is likely to have provided with a more homogeneous assessment. The number of TTTS presenting at stage I at the time of therapy was limited, as reported in the original RCT, and one could argue that our conclusions cannot be extrapolated to stage I.
      In conclusion, TTTS treated with FSLC is associated with a lower incidence of death and long-term major neurological impairment than AD. The objective of fetal therapy should be to reach a high percentage of intact survival. Although the short-term benefit of FSLC was already established, the present study confirms that it is also associated with higher intact survival up to the age of 6 years. This provides important information for counselling parents at the time of the diagnosis of TTTS and making a decision for treatment in relation to both short-term and long-term follow-up–related issues.

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      Linked Article

      • Long-term neurodevelopmental outcome in TTTS in the Eurofoetus trial
        American Journal of Obstetrics & GynecologyVol. 205Issue 2
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          We wish to congratulate the authors on their important study on long-term outcome in the Eurofoetus trial.1 The authors found a similar rate of cerebral palsy (CP) between the fetoscopic selective laser coagulation (FSLC) and the amniodrainage (AD) group, 13% (9/69) and 15% (6/41), respectively (rates of CP are higher than the reported rates1 because we excluded children lost to follow-up, n = 10).
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