Objective
We sought to identify differences in echocardiographic profiles of monochorionic (MC)/diamniotic (DA) pregnancies with early or mild twin-twin transfusion syndrome (TTTS), compared to MC/DA twins affected only by discordant growth or discordant fluid.
Study Design
This was a retrospective evaluation of sonograms and echocardiograms of twin pregnancies referred for suspected TTTS.
Results
A total of 112 MC/DA pairs were studied. In all, 41 did not have/develop TTTS, and 61 had stage I/II TTTS. Ten developed TTTS after initially not meeting criteria. TTTS recipients had a higher rate of venous Doppler or tricuspid inflow abnormalities than purported recipients in non-TTTS pregnancies (86% vs 37%, P < .001). TTTS recipients had shorter tricuspid inflow duration/R-R intervals than non-TTTS fetuses (32 ± 6% vs 37 ± 4%, P < .001). Logistic regression and recursive partitioning identified shorter tricuspid inflow duration, longer isovolumic relaxation, and ductus venosus abnormality associated with TTTS.
Conclusion
Diastolic pathology, specifically shorter tricuspid inflow duration, may be considered a hallmark of TTTS distinguishing these pregnancies from other MC/DA twin complications.
Twin-twin transfusion syndrome (TTTS) is a complication that occurs in at least 10% of monochorionic (MC) twin pregnancies. The clinical diagnosis of TTTS is made sonographically by presence of concurrent polyhydramnios (maximum vertical pocket ≥8 cm) in the recipient and oligohydramnios (≤2 cm) in the donor twin; varying degrees of cardiac dysfunction may be seen in the recipient. The pathophysiology of the syndrome itself and of the development of cardiomyopathic changes remains incompletely understood. It is widely believed that volume overload in combination with exposure to abnormal vasoactive mediators results in cardiac hypertrophy and cardiomegaly, with cardiac dysfunction (and ultimately hydrops) in the recipient. Treatment of TTTS with selective fetoscopic laser photocoagulation or serial amnioreduction has dramatically improved survival and outcomes in affected pregnancies. Selective fetoscopic laser photocoagulation in particular has been shown to significantly improve cardiovascular pathology seen antenatally in the recipient twin.
The Quintero staging criteria for TTTS were established in 1999 to help stratify signs on clinical presentation (polyhydramnios ≥8 cm/oligohydramnios ≤2 cm, presence/absence of visible bladder in the donor, Doppler abnormalities, and hydrops) by level of severity. However, some MC pregnancies may be affected by discordant amniotic fluid and/or discordant growth but do not manifest TTTS (as per the criteria defined by Quintero), and some pregnancies meeting criteria for early or mild (stage I-II) TTTS will not progress to higher stages even without treatment.
The goal of the current investigation was to establish an echocardiographic profile unique to pregnancies that meet criteria for early or mild TTTS (without hydrops or overt umbilical venous [UV] Doppler abnormality), which would distinguish these twins from those affected only by discordant growth or discordant amniotic fluid volume without TTTS. We hypothesized that diastolic myopathic changes as defined by Doppler echocardiography would be present in recipient twins with stage I and II TTTS but absent in MC twin pairs referred for suspected TTTS but determined not to meet criteria after ultrasound evaluation at our institution. Further, we aimed to investigate on a longitudinal basis whether these Doppler abnormalities might already be present at initial evaluation in the subset of recipient twins not initially meeting TTTS ultrasound criteria but subsequently developing the disease. These findings would potentially give further insight into early cardiac pathology in TTTS.
Materials and Methods
Databases of the Fetal Treatment Center and Fetal Cardiovascular Program at the University of California, San Francisco, were queried for pregnancies referred for suspected TTTS from January 2006 through July 2009. All pregnancies undergoing fetal echocardiography and obstetrical ultrasound on the same day were included. Sonographic examination for twin pairs included a detailed anatomic survey, measurement of deepest amniotic fluid pockets, placental cord insertion sites, Doppler evaluation of the umbilical artery and UV for each fetus, and attempt at placental vascular mapping. The ultrasound examinations for patients in this study were retrospectively reviewed by 2 of the investigators (V.A.F., L.R.) blinded to initial staging and to pregnancy outcome. Patients were diagnosed with TTTS if polyhydramnios ≥8 cm and oligohydramnios ≤2 cm was present, and were staged as per the aforementioned Quintero criteria. Patients were assigned to the non-TTTS group if the above criteria for polyhydramnios and oligohydramnios were not met, irrespective of bladder or Doppler information and estimate fetal weight discrepancy.
Fetal echocardiograms were performed on ultrasound systems (Acuson Sequoia C256 and C512; Siemens, Mountain View, CA) using a combination of curvilinear and phased-array probes operating at 6-8 MHz. All studies included a full 2-dimensional evaluation of cardiac structure and systolic ventricular function with full pulsed wave and color Doppler examination including venous and umbilical cord interrogation.
Echocardiograms were retrospectively reviewed by a single fetal echocardiographer (A.J.M.G.) blinded to pregnancy outcome. Diastolic function was assessed by evaluation of tricuspid and mitral inflow patterns and venous Doppler waveforms as follows. Tricuspid inflow was considered normal if there were distinct E and A waves and abnormal if there was marked fusion of the E and A waves or if the waveform was monophasic ( Figure 1 ). Ductus venosus (DV) Doppler pattern was considered markedly abnormal if there was reversal of flow with atrial contraction at any time during the examination; if reversal was not present, measurement of the peak velocities of the S and a waves were measured and expressed as a ratio (DV S:a ratio) ( Figure 2 , A), with a ratio of >3:1 considered abnormal. Inferior vena cava or hepatic vein Doppler forward to reverse flow velocity-time integral (VTI) was measured ( Figure 2 , B), with a reversal of >20% of forward flow considered abnormal. UV Doppler pattern was considered normal if continuous ( Figure 2 , C) and abnormal if there was transient decrease in flow velocity corresponding with atrial contraction on any tracing obtained during the examination. The left ventricular (LV) isovolumic relaxation time (IVRT) was measured as the time interval from aortic valve closure to the onset of mitral valve inflow ( Figure 2 , D). Tricuspid inflow duration as a percentage of cardiac cycle length (TV/RR) and mitral inflow duration as TV/RR were determined by measurement of the total inflow time divided by the time from onset of inflow signal to the time of onset of the subsequent inflow signal ( Figure 3 ). All Doppler quantification measurements were performed on 2-3 consecutive beats during fetal apnea and averaged.
Right ventricular (RV) diastolic dysfunction, as a composite analysis, was defined as presence of any one of the following: markedly fused or monophasic tricuspid inflow Doppler, abnormal UV or DV Doppler pattern, or inferior vena cava flow reversal VTI >20% of forward flow VTI.
Statistical analysis
Descriptive statistics such as the mean, median, and SD and interquartile ranges were calculated using Microsoft Excel for Macintosh, version 11.2.3. Fisher exact tests were used to compare categorical variables between non-TTTS and TTTS twins; eg, presence/absence of RV diastolic dysfunction (as defined above) or LV IVRT above or below 50 milliseconds.
Multivariable logistic regression analysis (multiple predictor variables) was performed to determine an optimal set of predictors using the glm function in R ( http://www.r-project.org/ ). The outcome was TTTS group and the predictor variables considered were TV/RR, inferior vena cava forward to reverse flow, mitral inflow duration, LV IVRT, UV, and DV S:a ratio. The diastolic parameter predictors present in the abnormal RV diastolic function profile were treated as continuous rather than categorical variables. Predictors were dropped from the model if their associated P value was > .1. The model was finally refitted with the reduced set of predictors. Results of the final model were reported as statistically significant if the predictor variable had an associated P value < .05.
In addition, recursive partitioning analysis for predicting TTTS group was performed with the same full set of predictor variables as above (using the rpart library in R). The parameters of the rpart function were set to defaults: priors proportional to the data counts, losses of 1, splits of type “gini”, and costs of 1.
This study was approved by the University of California, San Francisco, Committee on Human Research.
Results
Patients
During the study period, 220 pregnancies were referred for evaluation at our center for possible TTTS. Fifty-four were either not evaluated or were excluded due to dichorionic placentation or death of a cotwin prior to arrival at our center, 8 with TTTS had emergent operative procedures without echocardiography, 7 with TTTS had termination of pregnancy without echocardiography, and 28 with ultrasound evaluation did not have TTTS by Quintero criteria and echocardiographic evaluation was cancelled (8 with no abnormality on ultrasound, 13 with discordant weights, 7 with fluid discordance–usually polyhydramnios in one and normal fluid in the other). This resulted in a cohort of 123 twin pairs with an echocardiogram performed on the same day as the ultrasound examination and available for review. Eleven had advanced TTTS on review of their initial obstetric ultrasound (Quintero stage III-V) and were excluded from analysis. The remainder comprise the study group (n = 112).
Clinical and ultrasound findings
Gestational age at evaluation, ultrasound assignment, Quintero staging, and pregnancy outcomes are presented in Table 1 . Sixty-one twin pairs had TTTS stage I or II at presentation (TTTS group). Fifty-one pregnancies did not meet criteria for TTTS at initial evaluation; of these, 41 never developed TTTS criteria (non-TTTS group). The other 10 subsequently developed TTTS during follow-up, and are analyzed separately.
| Characteristic | Value |
|---|---|
| Mean EGA at evaluation, wk (range) | |
| Entire cohort | 20.2 (15.9–28.7) |
| Non-TTTS | 20.6 (15.9–28.7) |
| TTTS I and II | 20.1 (15.9–25.1) |
| TTTS after initial negative evaluation | 19.7 (16–23) |
| Ultrasound assignment a | |
| Non-TTTS | 41 |
| TTTS on initial evaluation | 61 |
| Quintero stage I | 18 |
| Quintero stage II | 43 |
| TTTS after initial negative evaluation | 10 |
| Survival non-TTTS (n = 29) | |
| Dual | 28 (97%) |
| Single | 0 |
| Survival TTTS (n = 58, terminations not included) | |
| Recipient | 43 |
| Donor | 42 |
| Dual | 40 (69%) |
| Single | 5 (9%) |
| Neither | 13 (22%) |
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