Objective
To identify risk factors for cerebral lesions among survivors of twin-twin transfusion syndrome treated with laser surgery.
Study Design
A multilevel regression analysis examined risk factors for neonatal cerebral lesions identified by imaging. Imaging was routine in “high-risk survivors,” defined as those delivered at <32 weeks’ gestation, and by clinical indications if born later. Severe lesions were defined as: intraventricular hemorrhage grade III-IV, cystic periventricular leukomalacia, ventriculomegaly and/or hydrocephalus, microcephaly, infarctions, porencephalic/Dandy-Walker cysts, or bilateral other cysts.
Results
For 262 consecutive laser-treated twin-twin transfusion syndrome patients, 18 neonates had severe lesions identified among 427 individual survivors (4.2%) and 242 “high-risk survivors” (7.4%). Forty-six newborns had any cerebral lesion, resulting in lesion rates of 10.8%-19.0%. Delivery <32 weeks’ (odds ratio, 4.95; P < .001) and <28 weeks’ (odds ratio, 6.25; P < .001) gestation were associated with increased likelihood of any cerebral lesion.
Conclusion
This cohort showed low rates (4-7%) of severe neonatal cerebral lesions, with prematurity being the primary risk factor.
Twin-twin transfusion syndrome (TTTS) occurs in monochorionic twin gestations because of unbalanced exchange of blood through placental vascular communications. The optimal treatment for TTTS is selective laser photocoagulation of communicating vessels (SLPCV), which has led to improved single and dual twin survival. With this improvement in survival, concern exists regarding risk factors to neonatal neurologic status and later neurodevelopmental outcomes.
There is a relative paucity of data regarding neurologic outcomes after laser surgery, particularly involving US patients. In a systematic review and metaanalysis of neurodevelopmental outcomes after laser therapy for TTTS published in 2011, 7 articles were identified that described neonatal neurologic outcomes. Overall, the prevalence of neurologic morbidity, defined as cerebral injury on imaging, cerebral palsy, blindness, and/or deafness, was 6.1%. Studies with particular emphasis on neonatal cerebral imaging have shown rates of severe cerebral lesions of 5-14%. The 2011 metaanalysis also showed that the prevalence of long-term neurodevelopmental impairment was 11.1%, with rates of cerebral palsy in the range of 4-6%. Thus, counseling of prospective TTTS patients contemplating laser surgery must take into account survival statistics as well as potential neurologic morbidity. Elucidation of the types of cerebral lesions and the antecedent factors would enhance parental counseling and decisions regarding treatment.
The aim of this study was to determine the prevalence of neonatal cerebral lesions and risk factors among TTTS survivors treated with laser surgery in a large cohort of US patients.
Materials and Methods
Study population
All consecutive patients that were treated for TTTS between March 2006 and May 2011 were considered eligible for this retrospective study. TTTS was diagnosed at initial assessment at Los Angeles Fetal Therapy (University of Southern California) if the monochorionic-diamniotic multiple gestation had a maximum vertical pocket of fluid ≥8 cm in the recipient’s sac and ≤2 cm in the donor’s sac. Each case was prospectively classified according to the Quintero staging system. Patients were not offered laser surgery if preoperative ultrasound revealed abnormal intracranial findings, including intraventricular hemorrhage (IVH), porencephalic cysts, hydrocephalus, isolated ventriculomegaly (atrium >20 mm), or congenital anomaly including Dandy-Walker syndrome, holoprosencephaly, and agenesis of the corpus callosum. All cases were exclusively treated via SLPCV with or without sequential technique, as described in detail previously. Umbilical cord occlusion is not a treatment option for TTTS at this center.
After laser surgery, the patients were referred back to their perinatologists for further pregnancy management. Delivery and 30-day survival information were collected at their respective intervals. Placental pathologic evaluation and injection studies were performed using previously reported methodology. Medical records of delivery, neonatal course, and all identified imaging reports were retrieved and reviewed. With few exceptions, neonates with a gestational age (GA) <32 weeks had routine cerebral imaging, and neonates with a GA ≥32 weeks had cerebral imaging when clinically indicated or deemed appropriate by the neonatal intensive care unit (NICU) team. “High-risk survivors” were defined as (1) those delivered at a GA <32 weeks, and (2) those delivered later for whom cerebral imaging was performed because of a clinical indication. Cerebral imaging was defined as a postnatal intracranial ultrasound, computed tomograph (CT) scan, and/or magnetic resonance imaging (MRI). Reported results defaulted to the confirmatory scans. This study was approved by the Institutional Review Board of the Health Sciences Campus of the University of Southern California.
Measures
Potential risk factors measured at the individual (ie, fetal) level included donor status (1 = donor, 0 = recipient) and birthweight (kg). Potential risk factors measured at the pregnancy level (ie, measurements that would be identical within a pair of twin fetuses) included Quintero stage (ordinal with range 1–4); gestational ages at diagnosis, surgery, and birth (in weeks); existence of a triplet (1 = triplet pregnancy, 0 = no triplet); cotwin intrauterine fetal demise (1 = cotwin fetal demise, 0 = no fetal demise); and presence of residual vascular anastomoses via placental injection studies (1 = residual anastomoses, 0 = no residual anastomoses). GA at birth was also recoded into a binary indicator of prematurity under 32 weeks (1 = age <32 weeks, 0 = age ≥32 weeks) and under 28 weeks (1 = age <28 weeks, 0 = age ≥28 weeks). All “singletons” of triplet gestations (ie, the triplet not involved in the fetofetal transfusion) were excluded from the analysis; however, the analysis did include twin survivors of triplet gestations.
For the cerebral lesion outcomes, “any lesions” were defined as: IVH, cystic periventricular leukomalacia (PVL), ventriculomegaly and/or hydrocephalus, microcephaly, single or multiple infarctions, congenital anomalies, porencephalic or Dandy-Walker cysts, nonspecific echogenicity, and bilateral/multiple subependymal, pseudo-, or choroid plexus cysts identified on neonatal imaging (coded 1 = any lesion, 0 = no lesion). “Severe lesions” excluded cases with only grade I-II IVH and/or nonspecific echogenicity. Unilateral subependymal, pseudo-, and choroid plexus cysts were not included in “any lesions” and excluded from the analysis as incidental findings.
Statistical analyses
SPSS (version 19; SPSS Inc, Chicago, IL) was used for data management and reporting of univariate statistics. Mplus software (version 6; Muthén & Muthén, Los Angeles, CA) was used to perform multilevel logistic regression analysis, also known as hierarchical linear modeling or hierarchical regression analysis, with twins grouped or “nested” within pregnancy. In the current study, a multilevel approach accounts for shared variance within twin pairs, which is created by pregnancy and family factors that are equivalent among the twins, as well as for heterogeneity between pregnancies and families. In this way, multilevel analysis allows us to simultaneously model the effects of both individual (ie, fetus level) and pregnancy-level risk factors on the likelihood of cerebral lesion development.
Regression models initially included donor status and birthweight at the individual level and Quintero stage, gestational ages at diagnosis, surgery, and birth, existence of a triplet, cotwin demise, and presence of residual vascular anastomoses at the pregnancy level. Because of the very low incidence of severe cerebral lesions among neonatal survivors in this cohort, risk factors to severe lesion development were not investigated further. Thus, only the presence of any lesion was regressed on the individual- and pregnancy-level risk factors. Risk factors to any lesion development were first tested individually (unadjusted model) and then simultaneously (adjusted model), and nonsignificant predictors were systematically removed from the adjusted model.
Results
A total of 262 consecutive TTTS cases were treated via SLPCV between March 2006 and May 2011. Of the 262 twin gestations, 242 (92%) had at least 1 neonatal survivor and 185 (71%) had dual survivors at 30 days. All demises before 30 days after birth, whether intrauterine (n = 78) or in the neonatal period (n = 19), were excluded from the analysis. Of the 427 “total survivors,” 137 were delivered at a GA of less than 32 weeks, and 134 of those had routine cranial ultrasounds. Of the remaining 290 30-day survivors that were born at or beyond 32 weeks’ gestation, 108 had cerebral imaging because of other clinical indications, and 182 had no clinical indication for imaging and thus did not undergo an imaging procedure. Thus, among our sample, 242 “high-risk survivors” had delivery, demographic, 30-day survivorship, and imaging information available for analysis ( Figure 1 ).
Among the entire cohort of 427 survivors, 46 (10.8%) had a documented cerebral lesion and 18 (4.2%) had a documented severe lesion if survivors with only grade I-II IVH and/or nonspecific echogenicity were excluded. All survivors with a documented cerebral lesion (n = 46) had a cranial ultrasound, except for 1 who had MRI only. Of the 45 survivors with a cranial ultrasound, 12 had an additional follow-up MRI and 2 others had follow-up CT scan. Among the 242 “high-risk survivors” indicated for cerebral imaging, the rates for any cerebral lesion and severe cerebral lesion were 19.0% and 7.4%, respectively. In this subgroup of “high-risk survivors,” the prevalence of any cerebral lesion and severe cerebral lesion in the survivors born between 24 to <28 weeks was 44.7% and 18.4%; between 28 and <32 weeks was 20.8% and 7.3%; and 32 weeks or greater was 8.3% and 3.7%, respectively ( Figure 2 ).
Table 1 presents descriptive statistics for the risk factors and outcomes by donor/recipient status and overall for the “high-risk survivors.” Multiple lesions were found in several of these survivors. Documented severe lesions included: grade III or IV IVH (n = 6; 2.5%), PVL (n = 7; 3%), ventriculomegaly/hydrocephalus (n = 6; 2.5%), microcephaly (n = 1; 0%), Dandy-Walker cyst (n = 1; 0%), and bilateral or multiple choroid plexus cysts (n = 1; 0%). No survivors were diagnosed with single or multiple infarctions. There were 7 survivors with residual anastomoses; among these, 2 had grade I-II IVH and 1 had a cotwin with an intrauterine fetal demise (IUFD) but no lesions. None of the survivors with residual anastomoses had severe lesions. No significant difference in the rate of any cerebral lesion were noted in the subgroup of “high-risk survivors” with an IUFD (7.7%) compared with those with dual survivors (20.4%, P = .18). Similarly, no difference in prevalence of severe cerebral lesions were detected in these 2 subgroups (3.8% vs 7.9%, P = .70, respectively).
| Variable | Donors, n (%) or mean (SD) | Recipients, n (%) or mean (SD) | Overall, n (%) or mean (SD) |
|---|---|---|---|
| Individual-level | |||
| Donor status | 111 (46) | 131 (54) | 242 (100) |
| Birthweight, kg | 1.33 (0.53) | 1.64 (0.56) | 1.50 (0.57) |
| Pregnancy-level | |||
| GA diagnosis | 20.74 (2.52) | 20.57 (2.54) | 20.65 (2.52) |
| GA surgery | 20.81 (2.50) | 20.65 (2.51) | 20.72 (2.51) |
| GA birth | 31.32 (3.09) | 31.30 (3.15) | 31.31 (3.12) |
| Prematurity <32 wks | 61 (55) | 73 (56) | 134 (55) |
| Quintero stage | |||
| Stage I | 17 (15) | 18 (14) | 35 (14.5) |
| Stage II | 21 (19) | 24 (18) | 45 (19) |
| Stage III | 62 (56) | 75 (57) | 137 (57) |
| Stage IV | 11 (9) | 14 (11) | 25 (10) |
| Triplet pregnancy | 9 (8) | 12 (9) | 21 (9) |
| Cotwin demise | 5 (4.5) | 21 (16) | 26 (11) |
| Residual anastomoses | 3 (3) | 4 (3) | 7 (3) |
| Outcome | |||
| Any lesion | 22 (20) | 24 (18) | 46 (19) |
| Severe lesion | 10 (9) | 8 (6) | 18 (7) |
| IVH (any) | 16 (14) | 21 (16) | 37 (15) |
| IVH (grade 1-2) | 12 (11) | 19 (15) | 31 (13) |
| IVH (grade 3-4) | 4 (4) | 2 (2) | 6 (2.5) |
| PVL-cystic | 4 (4) | 3 (2) | 7 (3) |
| Ventriculomegaly/hydrocephalus | 4 (4) | 2 (2) | 6 (2.5) |
| Microcephaly | 1 (1) | 0 (0) | 1 (0) |
| Single or multiple infarctions | 0 (0) | 0 (0) | 0 (0) |
| Porencephalic/Dandy-Walker cysts | 1 (1) | 0 (0) | 1 (0) |
| Bilateral or multiplechoroid plexus cyst | 0 (0) | 1 (1) | 1 (0) |
| Single choroid plexus cyst | 5 (5) | 6 (5) | 11 (4.5) |
| Subependymal or pseudocyst | 0 (0) | 4 (3) | 4 (2) |
| Nonspecific echogenicity | 1 (1) | 2 (2) | 3 (1) |
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