Predictors of 2-year cognitive performance after laser surgery for twin-twin transfusion syndrome


The purpose of this study was to determine risk factors for poor cognitive performance among children who are treated with in utero selective laser photocoagulation of communicating vessels for twin-twin transfusion syndrome.

Study Design

This was a prospectively enrolled cohort study. Cognitive performance at age 2 years (±6 weeks) was assessed with the Battelle Developmental Inventory 2nd Edition (BDI-2). Multilevel regression models evaluated risk factors for poor cognitive performance at shared (pregnancy) and individual (child) levels. In addition to development, blindness, deafness, and cerebral palsy were assessed based on physical examination. A priori power analysis determined that a sample of ≥100 children was required for adequate statistical power (0.80).


One hundred children (57 families) were evaluated. Total BDI-2 score was within normal range (mean, 101.3 ± [SD]12.2); 1 child had a BDI-2 score of <70. Individual child-level risk factors for lower BDI-2 included male sex (β = –0.37; P < .01), lower head circumference (β = 0.28; P < .01), and higher diastolic blood pressure (β = –0.29; P < .01). At the pregnancy level, lower maternal education (β = 0.60; P < .001), higher Quintero stage (β = –0.36; P < .01), and lower gestational age at birth (β = 0.30; P < .01) were associated with worse cognitive outcomes. Donor/recipient status, gestational age at surgery, fetal growth restriction, and co-twin fetal death were not risk factors. The rate of neurodevelopmental impairment (blindness, deafness, cerebral palsy, and/or a BDI-2 score <70) was 4%.


Overall cognitive performance quotients were in the normal range, with risk factors for poor outcomes seen at the pregnancy and child levels. Clinical and socioeconomic characteristics can identify at-risk children who need additional interventions.

Twin-twin transfusion syndrome (TTTS) arises in monochorionic twin gestations because of unequal exchange of blood through the placental vascular communications. Selective laser photocoagulation of communicating vessels (SLPCV), which results in improved prenatal and perinatal survival, is the preferred treatment for TTTS. With enhanced survival, identification of risk factors to later cognitive performance and outcomes becomes critical. However, few studies have reported risk factors that are associated with long-term developmental outcomes among infants with TTTS after laser surgery; none of the studies have been in the United States.

Although neonatal neurologic outcomes have been characterized, there is a lack of data on developmental outcomes after laser surgery in US patient cohorts. A recent systematic review and metaanalysis identified 8 international studies that reported long-term developmental outcomes after laser therapy for TTTS outside the perinatal period. In this metaanalysis, prevalence of nonperinatal neurologic morbidity, abnormal standardized test of neonatal development, or both was 11.1%; rates of cerebral palsy were in the range of 4-6%. In counseling mothers who carry fetuses with TTTS and who are eligible for SLPCV, a clear understanding of perinatal neurologic morbidity and longer-term developmental outcomes is needed. Elucidation of the antecedent risk factors would enhance clinical and parental decision-making regarding treatment and prospective screening.

To that end, the aim of this study was to describe the risk factors that are associated with poor developmental outcomes of survivors who were treated in utero with laser surgery in a large cohort of US patients at 2 years of age. Based on the previous research, we hypothesized that lower gestational age at birth, later gestational age at time of procedure, higher Quintero stage, lower birthweight, and donor twin status will result in poorer cognitive performance.

Materials and Methods

Study population

All consecutive patients who were treated for TTTS between December 2007 and May 2010 were considered eligible and were contacted for this 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 classified prospectively according to the Quintero staging system. All patients were given the options of expectant treatment, pregnancy termination, amnioreduction, laser surgery, or selective reduction (at another center). Patients with stage I TTTS were informed of the controversy of undergoing laser surgery and were offered the option of expectant treatment with laser surgery only for disease progression. Patients were not offered laser surgery if preoperative ultrasound scans revealed gross abnormalities of intracranial anatomy. Cases were treated exclusively by SLPCV with or without sequential technique, as described in detail previously.

All consecutive laser-treated TTTS patients during the study period were contacted before the time their child was to reach 2 years old (± 6 weeks) corrected for gestational age and invited to participate by a study nurse, who was blinded to the predictors. Reasons that patients declined participation were recorded. All subjects were evaluated in the Southern California Clinical Translational Science Institute’s Clinical Trials Unit at Children’s Hospital Los Angeles, which is an institution independent and physically separated from Los Angeles Fetal Therapy. Families were given an incentive per child of $25 for their participation. There was no travel budget.

This study was approved by the institutional review board of the Health Sciences Campus of the University of Southern California and the Committee on Clinical Investigations at Children’s Hospital Los Angeles.


The Amiel-Tison Neurodevelopmental Examination was used to determine cerebral palsy by a board-certified developmental-behavioral pediatrician. This test is based on the clinical presence of gross and/or fine motor delay together with neurologic signs such as abnormal persistence of primitive reflexes, muscle tone, motor developmental progression, or coordination. Hearing and vision impairment was determined through the same examination or previous clinical report. Additionally, parent and child demographics, which included child height, weight, head circumference, and blood pressure, were collected at the 2-year-old visit.

A single board-certified neuropsychologist who was masked to the subjects’ clinical characteristics evaluated the cognitive and developmental status of participants with the Battelle Developmental Inventory, Second Edition (BDI-2). This tool was selected on the basis of availability of normative data, targeted age range, and the availability of standardized versions in both English and Spanish languages. A Spanish translator assisted the neuropsychologist with the administration of the BDI-2 as needed. Patients and their twin cohort (if applicable) were assessed consecutively on the same day at approximately 2 years of age (±6 weeks). Consistent with standardized administration of the BDI-2, each participant was assessed in the presence of 1 primary caretaker. In a few cases, the participant was unable to tolerate physical separation from their twin, who was then allowed to be present (playing separately) in the examination room.

The BDI-2 involves direct individual assessment and parental interview to measure key developmental skills in children from birth to 95 months (7 years, 11 months). Based on widely accepted developmental milestones for children, the BDI-2 assesses 5 developmental subdomains (personal-social, adaptive, motor, communication, and cognition) comprising overall development. The total BDI-2 developmental quotient score is computed as a sum of the 5 BDI-2 subdomains, and it has a mean of 100 with standard deviation of 15. Individual item scores range from 0-2 points, with scores based on 1 of 3 predetermined criteria that include observation, parent interview, and/or performance on a structured task.

Neurodevelopmental impairment (NDI) was defined as having bilateral blindness (unable to fix on or track an object), bilateral deafness (requiring amplification), cerebral palsy (based on physical examination), and/or a BDI-2 total developmental quotient of <70 (standardized score), in accordance with previous TTTS literature.

Statistical analyses

Descriptive statistics and bivariate comparisons were produced with IBM SPSS Statistics software (version 19; SPSS Inc, Chicago, IL). Bivariate comparisons were also calculated between participating and not participating families and between donors and recipients (eg, t tests for continuous measures, chi-square tests for categoric variables). Multilevel linear regression analysis was conducted in Mplus software (version 6; Muthén & Muthén, Los Angeles, CA), with twins grouped or nested within pregnancy and missing data were subject to listwise deletion in the regression model. Unlike logistic regression, which describes the relationship between the presence or level of a predictor and the odds of obtaining a yes or 1 on the binary outcome variable, linear regression coefficients quantify the relationship between a predictor and the expected level or amount of a continuous outcome. Specifically, a standardized linear regression coefficient denotes the expected change in the (standardized) outcome for 1 standard unit change in the predictor. The multilevel approach extends the general linear regression model by accounting for the genetic and environmental experience that is shared by twins of the same family (the shared or pregnancy level) and the experiences that are unique to each child (the individual or child level). Multilevel regression allows for simultaneous inclusion of the effects of both child-level and pregnancy-level risk factors of cognitive performance; further, it supports the inclusion of families with 2 (twin) children and families with only 1 surviving child.

Because of the small number of children with NDI, the total BDI-2 developmental quotient score was considered the primary outcome for analysis. Child-level risk factors for development that were tested in the regression models included donor status (donor = 1; recipient = 0), male sex (male = 1; female = 0), height (centimeters), weight (kilograms), head circumference (centimeters), systolic and diastolic blood pressure (millimeters of mercury), and heart rate (beats per minute). Pregnancy-level risk factors included gestational age at surgery and birth in weeks, the twins’ current corrected age in years, Quintero stage, presence (1) or absence (0) of fetal growth restriction, fetal death, and complications at delivery, maternal and paternal age in years, maternal and paternal education (some college or more = 1; high school or less = 0), number of adults and children in the home, parents’ marital status (married = 1; other = 0), minority race/ethnicity (minority = 1; white = 0), and whether the twins’ mother or father smokes tobacco (yes = 1; no = 0). Although all potential risk factors for poor cognitive performance initially were incorporated into the adjusted model, it was expected that some demographic covariates would not be related to the outcome. Thus, nonsignificant predictors were removed systematically to arrive at the most parsimonious possible final model. The study was powered on the basis of the assumption of a relatively parsimonious random effects regression model with at most 10 predictors at either level. In such a model with alpha level of .05 and adequate power of 0.80, a priori power analysis determined that a total sample of 100 children was required to detect small-to-moderate regression effects.


One hundred thirty consecutive TTTS cases were treated by SLPCV between December 2007 and May 2010; 90 families resided in California. Fifty-seven families comprising 100 eligible children were enrolled in the study. Fourteen co-twins from these families did not survive the prenatal or neonatal period and were unable to be assessed at the 2-year follow-up time point. The rate of study participation for in-state families was 58% vs 13% for out-of-state families ( P < .001). The following reasons were given by the remaining 73 families who did not participate in the study: lived too far (n = 32), unable to contact (n = 21), no survivors (n = 8), unable to accommodate (n = 5), uninterested (n = 3), language barrier (n = 2), last minute cancellation (n = 1), and motor vehicle accident (n = 1). Table 1 presents the characteristics of families by study participation. There were no statistically significant differences seen in the numbers of donors and recipients, Quintero stage distribution, pregnancies with intrauterine fetal death, pregnancies with donor intrauterine growth restriction, or gestational ages at surgery or birth between families who did and did not participate.

Table 1

Characteristics of study participants vs nonparticipants

Characteristics Not enrolled Enrolled Significance test
Total families, n 73 57
Total eligible children, n 106 100
Donors, n 46 (43%) 49 (49%) χ 2 (1) = 0.65; P = .42
Recipients, n 60 (57%) 51 (51%)
Quintero stages, n χ 2 (3) = 3.517; P = .32
1 8 (11%) 10 (18%)
2 14 (19%) 13 (23%)
3 39 (53%) 30 (53%)
4 12 (16%) 4 (7%)
Pregnancies with fetal death, n 20 (27%) 9 (16%) χ 2 (1) = 2.488; P = .11
Donors with growth restriction, n 32 (44%) 23 (40%) χ 2 (1) = 0.159; P = .69
Gestational age, wk a
Surgery 20.55 ± 2.20 20.47 ± 2.62 t (128) = 0.189; P = .85
Delivery 31.76 ± 4.57 32.96 ± 3.62 t (128) = 1.624; P = .11

Vanderbilt. Two-year cognitive performance in TTTS. Am J Obstet Gynecol 2014 .

a Data are given as mean ± SD.

Descriptive statistics for parent factors are given in Table 2 ; child risk factors and cognitive performance are given in Table 3 by donor/recipient status and overall designation. Recipients weighed more at the 2-year visit (donors: mean weight, 11.65 ± 1.38 kg; recipients: mean weight, 12.62 ± 1.75 kg; t(98) = 3.095; P < .01). However, there were no other significant differences between donor and recipient twins.

Table 2

Pregnancy and family demographic level factors for enrolled families

Demographic Measure
Pregnancy factors
Quintero stage, n (%)
I 10 (17.5)
II 13 (23)
III 30 (52.6)
IV 4 (7)
Any complications, n 41 (72)
Vaginal delivery, n 9 (16)
Gestational age, wk a
Delivery 32.96 ± 3.62 (24–38.7)
Surgery 20.47 ± 2.62 (16.4–26)
Parent/family factors (n = 57)
Married, n (%) 43 (74)
Maternal high school education or less, n (%) 13 (23)
Paternal high school education or less, n (%) 20 (35)
Maternal smoking, n (%) 1 (2)
Paternal smoking, n (%) 5 (9)
Maternal age, y a 32.30 ± 6.33 (21–45)
Paternal age, y a 35.59 ± 7.98 (22–52)
Adults in home, n a 2.37 ± 0.85 (1–5)
Children in home, n a 2.94 ± 1.33 (0–6)

Vanderbilt. Two-year cognitive performance in TTTS. Am J Obstet Gynecol 2014 .

a Data are given as mean ± SD (range).

May 10, 2017 | Posted by in GYNECOLOGY | Comments Off on Predictors of 2-year cognitive performance after laser surgery for twin-twin transfusion syndrome
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