Background
The persistent changes in cardiac structure and function in children who survived twin-to-twin transfusion syndrome remain a matter of concern and controversy. Current fetal echocardiographic parameters and their postnatal evolution can help improve our understanding of the subject.
Objective
To describe the echocardiographic changes of monochorionic fetuses affected by twin-to-twin transfusion syndrome, the recipient and the donor, before and after laser photocoagulation and to determine their evolution in the third trimester and during their first year of life.
Study Design
An observational study was conducted including 55 uncomplicated monochorionic diamniotic twins and 78 pairs with twin-to-twin transfusion syndrome, 44 stage I-II and 34 stage III-IV, prospectively enrolled from 2015 until 2018. Comprehensive echocardiography was performed at 4 time periods: before laser photocoagulation, at 24 to 72 hours after surgery, at 28 to 30 weeks of gestation, and at 6 to 12 months after birth. Echocardiographic parameters were transformed to z-scores or indexed for heart area, estimated fetal weight, or body mass surface.
Results
At diagnosis, recipients in all stages presented larger hearts (cardiothoracic ratio z-score: 2.77 [0.8] vs controls: −0.03 [0.5]; P <.001) and signs of ventricular hypertrophy (left end-diastolic ventricle wall thickness: 2.68 [0.7] vs controls −0.03 [0.7]; P <.001), along with systolic (cardiac index recipients: 317 [114] mL/min/kg vs controls: 400 [120] mL/min/kg, P <.001) and diastolic impairment (isovolumetric relaxation time z-score: 2.76 [0.6] vs controls: 0.05 [0.6]; P <.001). Donors presented smaller ventricular areas and diameters when compared with controls (left end-diastolic ventricle area z-score: −1.48 [1] vs 0.03 [0.9]; P <.001), along with decreased longitudinal motion (tricuspid annular plane systolic excursion z-score: −0.9 [1] vs controls −0.04 [1]; P <.001) and shorter ejection time z-score (−1.5 [0.7] vs controls: 0.0 [0.7]; P <.001). After surgery, an improvement in functional parameters was observed in both fetuses, whereas most morphometric changes prevailed in donors and recipients in the prenatal period. Postnatally, cardiac remodeling persisted in recipients (left relative wall thickness: 0.34 [0.02] vs controls: 0.30 [0.02]; P <.001), whereas donors mainly presented a decreased longitudinal motion in infancy (tricuspid annular plane systolic excursion z-score: −0.72 [0.7] vs controls: 0.23 [0.9]; P <.05).
Conclusion
Cardiac remodeling is present in both fetuses at the twin-to-twin transfusion syndrome diagnosis, whereas diastolic dysfunction is only significant in the recipient. Fetal therapy improves most echocardiographic parameters, although postnatally, the echocardiographic changes persist in both fetuses.
Introduction
Twin-to-twin transfusion syndrome (TTTS) complicates about 9% to 15% of monochorionic pregnancies. , TTTS is essentially a cardiovascular disorder that has a hemodynamic effect on both fetuses, even in the early stages of disease, by the imbalanced blood flow through the placental vascular anastomosis. However, the underlying mechanisms that trigger TTTS remain unclear. Whereas the recipients manage volume and pressure overload, the donors face a hypovolemic state stimulating the renin–angiotensin system (RAS), increasing vascular resistance in both fetuses through the vascular communications of the monochorionic placenta. , This is particularly harmful to the hypertensive recipient.
Why was this study conducted?
Current standards for fetal echocardiography allow a detailed assessment of cardiac morphometry and function, which is essential to defining fetal cardiac remodeling. Therefore, a contemporary and more comprehensive approach to assessing the cardiovascular hemodynamics of monochorionic twin fetuses complicated by twin-to-twin transfusion syndrome from diagnosis to early infancy is highly recommended.
Key findings
At the time of twin-to-twin transfusion syndrome diagnosis, recipients and donors demonstrated cardiac remodeling associated with systolic dysfunction, whereas diastolic dysfunction mainly occurred in the recipients. These changes continued after fetoscopic surgery. After birth, cardiac remodeling patterns persisted in recipients, whereas longitudinal motion remained altered in donor infants.
What does this add to what is known?
This study confirms previous findings of evident cardiac remodeling in recipients by adding modern and novel parameters regarding cardiac morphometry and function. Regarding donors, this study demonstrates the presence of morphometric remodeling together with systolic dysfunction. After birth, donors’ morphologic changes regressed, possibly because of volume/pressure restitution, but systolic impairment persisted. In recipients, cardiac remodeling persisted in early childhood, and further study and follow-up are important.
Laser photocoagulation of communicating vessels (LPCV) is the treatment of choice and the only curative intervention for TTTS in most cases, particularly those between 16 and 26 weeks’ gestation, in which both circulations are disconnected, with immediate effects on cardiac function when the intertwin volume imbalance ends and the vasoactive mediators’ exchange ceases. Advances in fetal echocardiography have encouraged the cardiovascular assessment of survivors. Efforts have been directed toward identifying the echocardiographic effects of TTTS, the hemodynamic impact of the LPCV treatment, , and the echocardiographic parameters that predict TTTS. ,
Prenatal cardiovascular effects of TTTS have been mainly described in recipients. , The volume and pressure overload and the consequent hypertension lead to an increased impedance and ventricular hypertrophy. This situation entails increased ventricular filling pressures, tricuspid regurgitation, and impaired relaxation. Regarding donors, recent evidence shows that these fetuses present signs of impaired systolic function such as decreased ventricular ejection force, strain rate, mitral annular plane systolic excursion, and increased myocardial performance index. After laser surgery, an improvement in cardiac function parameters has been profiled in recipients, , , whereas donors present transient signs of cardiac overload. , Overall, a normal cardiovascular assessment has been outlined in TTTS survivors if treated by fetoscopy at the 10-year follow-up, with only mild alterations in diastolic function detected using conventional Doppler and speckle-tracking techniques.
Nevertheless, a complete echocardiographic evaluation, integrating morphometric and functional parameters using the current standardized methodology in TTTS fetuses at diagnosis, after LPCV and early postnatal life, has not been performed. Such information may be valuable to understand better the physiopathology of the disease and consequently improve prenatal counseling and postnatal individualized clinical management in TTTS survivors. This study aims to compare TTTS fetuses with uncomplicated monochorionic diamniotic (MCDA) twin fetuses in terms of fetal cardiac morphometry and function at diagnosis, the cardiovascular effects of fetal surgery, and their evolution during late pregnancy and infancy.
Study Design
Study population and study protocol
Patients were recruited from January 2015 to November 2017 in the BCNatal Maternal-Fetal Medicine Department (Hospital Clinic and Hospital Sant Joan de Déu Barcelona). Ethical approval was obtained from our local ethics board (code HCB/2015/0484), and all participants provided written informed consent.
In this prospective observational study, consecutive TTTS pairs were matched by gestational age (GA) at the time of fetal ultrasound to uncomplicated MCDA twins. TTTS diagnosis was defined as the deepest vertical pocket of amniotic fluid <2 cm in the donor’s sac and ≥8 cm or ≥10 cm before and after 20 weeks in the recipient’s sac. The severity of TTTS was classified according to the staging system proposed by Quintero et al. TTTS stage I is defined when there is still a visible bladder in the donor, stage II when the donor no longer has a visible bladder, stage III when the blood flow is abnormal in either twin (absent/reverse diastolic flow in the umbilical artery of the donor or recipient and/or absent/reverse flow in the ductus venosus or pulsatile flow in the umbilical vein of the recipient), stage IV when there is hydrops, and finally stage V when at least 1 twin has died. Only TTTS cases that underwent selective LPCV along the intertwin vascular equator were included in the final analysis. The LPCV was performed using a diode laser through 8- to 10-Fr diameter trocars, housing 1- to 2-mm endoscopes and operative channels. Amniotic fluid was drained at the end of the surgery until the deepest vertical pocket in the recipient’s sac was <8 cm. Pregnancies were assigned into 1 of 3 groups: (1) uncomplicated MCDA; (2) TTTS Stages I+II; and (3) TTTS Stages III+IV.
The control group consisted of uncomplicated MCDA twin pregnancies that did not develop any complications during pregnancy; these were controlled every 2 weeks as part of standard prenatal surveillance. Study exclusion criteria included the presence of fetal malformation or a chromosomal anomaly, selective fetal growth restriction without TTTS, TTTS stage V, twin anemia-polycythemia sequence (TAPS), and monoamniotic and higher-order pregnancies. TTTS cases treated by cord occlusion were also excluded from the analysis.
Fetal echocardiographic evaluation was performed at the TTTS diagnosis and 24 to 72 hours after fetal surgery. Subsequently, in the third trimester between 28 and 32 weeks of gestation, a comprehensive echocardiography was performed in the survivors. In uncomplicated MCDA twin pregnancies, echocardiography was performed in 2 GA intervals: 17 to 23 weeks and 28 to 32 weeks of gestation.
Maternal and gestational characteristics were collected. Perinatal data, including GA at delivery, mode of delivery, birthweight, Apgar scores, and umbilical artery pH, were also collected. TTTS survivors and uncomplicated monochorionic infants were followed up for cardiovascular assessment between 6 and 12 months of age.
Fetal and infants’ cardiovascular assessment
The prenatal and postnatal echocardiographic assessment was performed as previously reported. , The methodology is detailed in the Supplemental Material A .
Fetal echocardiographic evaluation
Fetal echocardiography included comprehensive morphometrical and functional cardiac assessments, evaluated according to the standardized methodology recently described in the uncomplicated MCDA twin population. Cardiac morphometry included the cardiac, thoracic, ventricular, and atrial areas and the ventricular diameters. The cardiothoracic ratio and the atrial-to-heart ratios were also calculated. The ventricular sphericity indices were obtained dividing the ventricular longitudinal diameter by the basal diameter. The myocardial walls’ thickness was obtained using M-mode at end-diastole and end-systole, whereas the right relative wall thicknesses (RWTs) were calculated as (septal wall thickness + free wall thickness) / ventricular transverse diameter.
Diastolic function was evaluated by measuring the atrioventricular flows, estimating the E/A ratios and the isovolumetric relaxation time. Systolic function included the assessment of the mitral annular plane systolic excursion, the tricuspid annular plane systolic excursion (TAPSE), the shortening fraction (SF), the left ejection fraction (EF), and the right fractional area change (FAC). Global cardiac function included the study of left myocardial performance index (MPI) and cardiac output. The MPI was calculated as (isovolumetric contraction time + isovolumetric relaxation time) / ejection time. The cardiac outputs were calculated as π × (aortic or pulmonary diameter/2) 2 × (aortic or pulmonary artery systolic velocity-time integral) × heart rate. Cardiac index was calculated adjusting by estimated fetal weight (kg).
Cardiovascular assessment at 6 to 12 months of age
Infants’ cardiovascular evaluations were performed between 6 and 12 months of age and included blood pressure measurement, height, and weight at the time of examination. In preterm birth cases, age was corrected by the time of prematurity. Echocardiography was performed following a standardized protocol. The left atrium and ventricle volumes were measured and the left ventricular diameter, the left ventricle (LV) posterior wall, and the interventricular septum thickness. Relative wall thickness was calculated as: end-diastolic LV posterior wall thickness + end-diastolic septal wall thickness) / end-diastolic diameter.
LV EF and SF were also calculated. Tricuspid and mitral annular displacement were measured in an apical 4-chamber view by M-mode. Tricuspid and mitral E and A values were obtained, and the E/A ratios were calculated. Tissue Doppler was applied to record E,’ A,’ and S.’ Mitral lateral E/E’ ratios were calculated. Left isovolumetric relaxation time was obtained as a diastolic function parameter.
Statistical analysis
Stata/IC version 15.1 (StataCorp, College Station, TX) was used for the statistical analysis. The sample size was calculated to show a difference of 0.15 in the MPI values between uncomplicated monochorionic twins and TTTS recipients based on previous results. For a power of 80% and an α risk of 0.05 and 1:2 sampling ratio, at least 20 subjects per study group were required. Considering possible dropouts given that many patients were referred from other states or Spanish regions, a minimum of 30 MCDA pairs of twins were included in each group. Results are presented as the mean (standard deviation), median (interquartile range), or percentage. Differences were considered significant when P was <.05. Maternal baseline and perinatal characteristics were compared using the Student t test, Mann-Whitney U test, or Pearson chi-square test. The fetal echocardiographic parameters regression analysis was adjusted by estimated fetal weight (EFW) at ultrasound. The postnatal covariates were birthweight, delivery mode, GA at delivery, current weight, height, and body mass index (BMI). Main prenatal and postnatal echocardiographic parameters were transformed to z-scores according to fetal echocardiographic standards for MCDA twins and echocardiographic reference values for infants when available, adjusted for body surface area calculated by the DuBois formula.
Results
Baseline and perinatal characteristics
Figure 1 shows a flow diagram of the study population and the study design. The study groups had similar maternal baseline characteristics regarding maternal age, parity, socioeconomic status, smoking, and education. Results are shown in Table 1 .
| Maternal characteristics | Controls (n=55) | TTTS I-II (n=44) | TTTS III-IV (n=34) | P value |
|---|---|---|---|---|
| Age, y | 34 (27–39) | 34 (30–38) | 33 (29–38) | .279 |
| Maternal weight, kg | 61 (13) | 59 (11) | 62 (15) | .730 |
| Maternal height, m | 1.64 (0.1) | 1.62 (0.07) | 1.63 (0.08) | .244 |
| BMI, a kg/m 2 | 23 (22–25) | 22 (20–24) | 24 (21–27) | .156 |
| Smoking, % | 0 | 6.5 | 6.3 | .237 |
| White, % | 79.1 | 82.6 | 81.3 | .662 |
| Primiparity, % | 85.2 | 78.6 | 88.0 | .845 |
| Low socioeconomic level, % | 14 | 13 | 9.4 | .826 |
| University education, % | 60.5 | 71.7 | 66.9 | .096 |
a BMI was calculated as weight in kilograms divided by the square of height in meters.
Delivery and perinatal data are exhibited in Table 2 . TTTS pregnancies in stages III-IV were delivered at an earlier GA than those in stages I-II and uncomplicated MCDA pregnancies (mean, 32.3 weeks [SD, 3.9], 33.5 weeks [2.7], 36.1 weeks [3.2], respectively), with higher birthweight discordance (15%, 14%, 7%, respectively). TTTS pregnancies also showed higher prenatal use of steroids and lower birthweight than controls.
| Perinatal data | Controls (n=55) | TTTS I-II (n=44) | TTTS III-IV (n=34) | P value |
|---|---|---|---|---|
| Gestational age at delivery, wk | 36.1 (3.2) | 33.5 (2.7) | 32.3 (3.9) | .001 |
| Cesarean delivery, % | 65.5 (36) | 75 (33) | 85.3 (29) | .089 |
| Male, % | 47 | 53 | 49 | .104 |
| Steroids, % | 26 | 83 | 86 | .001 |
| Birthweight discordance, % | 7 | 14 | 15 | .023 |
| Larger twin (recipient) | ||||
| Birthweight, g | 2470 (433) | 2064 (412) | 1935 (533) | .001 |
| 5-min Apgar score | 10 (9–10) | 9 (8–10) | 9 (8–10) | .109 |
| Umbilical artery pH | 7.23 (0.1) | 7.22 (0.1) | 7.21 (0.06) | .231 |
| Smaller twin (donor) | ||||
| Birthweight, g | 2285 (417) | 1767 (628) | 1640 (632) | .001 |
| 5-min Apgar score | 10 (9–10) | 9 (8–10) | 9 (8–10) | .328 |
| Umbilical artery pH | 7.24 (0.05) | 7.19 (0.11) | 7.20 (0.02) | .031 |
Fetal assessment
Z-scores of the presurgical and postsurgical echocardiographic results are shown in Tables 3 and 4 . Echocardiographic evaluation in the third trimester is displayed in Table 5 . Complete analyses of echocardiographic parameters are exhibited Supplemental Tables 1 (presurgical), 2 (postsurgical), and 3 (third-trimester assessment). In Supplemental Table 4 are presented the echocardiographic parameters before and after fetoscopy in recipients and donors.
| Characteristic | Controls (n=110) | TTTS I-II | TTTS III-IV | ||
|---|---|---|---|---|---|
| Recipients (n=44) | Donors (n=44) | Recipients (n=34) | Donors (n=34) | ||
| Gestational age at scan, wk | 20.3 (3.9) | 20.1 (3.2) | 20.1 (3.2) | 20 (3.9) | 20 (3.9) |
| Estimated fetal weight at scan, g | 322 (179) | 307 (190) | 265 (165) a | 300 (189) | 257 (154) a |
| Echocardiography | |||||
| Cardiac and atrial dimensions | |||||
| Cardiothoracic ratio z-score | −0.03 (0.5) | 2.32 (0.8) a | 0.03 (0.5) | 3.22 (0.7) a | 0.34 (0.7) |
| Left atrial/cardiac ratio | 0.15 (0.05) | 0.17 (0.05) a | 0.15 (0.04) | 0.17 (0.06) a | 0.15 (0.05) |
| Ventricle dimensions and areas | |||||
| Left ventricular basal transverse diameter z-score | −0.02 (0.7) | 0.15 (1.21) | −0.85 (1.02) a | 0.26 (1.44) | −0.88 (1) a |
| Left ventricular longitudinal diameter z-score | 0.06 (0.5) | 0.16 (1.35) | −0.93 (1) a | 0.22 (1.1) | −1.12 (1) a |
| Left sphericity index | 1.81 (0.35) | 1.72 (0.48) a | 1.80 (0.34) | 1.70 (0.48) a | 1.79 (0.50) |
| Left end-diastolic ventricle area, z-score | 0.03 (0.9) | 0.41 (0.7) | −1.18 (0.9) a | 1.34 (0.4) | −1.78 (1) a |
| Left relative wall thickness | 0.72 (0.21) | 0.91 (0.3) a | 0.84 (0.21) | 1.06 (0.3) a | 0.86 (0.29) |
| Myocardial wall thicknesses | |||||
| Left end-diastolic ventricle wall thickness z-score | −0.03 (0.7) | 2.63 (0.7) a | 0.01 (0.5) | 2.77 (0.6) a | 0.02 (0.5) |
| Systolic function | |||||
| TAPSE z-score | −0.04 (0.5) | −0.72 (0.4) a | −0.87 (0.7) a | −1.05 (0.7) a | −0.94 (0.8) a |
| MAPSE z-score | 0.03 (0.5) | 0.03 (0.7) a | −0.49 (0.5) a | −0.81 (0.6) a | −0.92 (0.9) a |
| Isovolumetric contraction time z-score | 0.01 (0.8) | 2.34 (0.7) a | −0.04 (0.6) | 2.54 (0.7) a | −0.01 (0.5) |
| Ejection time z-score | 0.00 (0.7) | −0.02 (0.5) | −1.32 (0.8) a | −0.06 (0.8) | −1.67 (0.6) a |
| Myocardial performance index z-score | −0.01 (0.6) | 2.82 (0.8) a | 0.88 (0.8) a | 2.83 (0.7) a | 0.92 (0.6) a |
| Left ejection fraction z-score | 0.03 (0.4) | −0.45 (0.5) a | 0.00 (0.5) | −0.41 (0.7) a | 0.13 (0.3) |
| Right FAC z-score | 0.00 (0.6) | −0.71 (0.7) a | 0.1 (0.7) | −1.3 (0.7) a | −0.27 (0.8) |
| Volumes | |||||
| Combined cardiac output z-score | 0.02 (0.6) | −0.61 (0.9) a | −1.56 (1) a | −0.73 (0.7) a | −1.65 (0.5) a |
| Cardiac index mL/min/kg | 400 (120) | 320 (110) a | 254 (112) a | 314 (117) a | 257 (100) a |
| Diastolic function | |||||
| Isovolumetric relaxation time z-score | 0.05 (0.6) | 2.68 (0.6) a | 0.11 (0.7) | 2.84 (0.5) a | 0.28 (0.6) |
a P <.05 compared with controls. P value adjusted for estimated fetal weight at the time of ultrasound.
| Characteristic | Controls (n=110) | TTTS I-II | TTTS III-IV | ||
|---|---|---|---|---|---|
| Recipients (n=44) | Donors (n=39) | Recipients (n=30) | Donors (n=25) | ||
| Gestational age at scan, wk | 20.3 (3.9) | 20.1 (3.2) | 20.1 (3.2) | 20 (5.9) | 20 (5.9) |
| Estimated fetal weight at scan, g | 322 (179) | 307 (190) | 265 (165) a | 300 (189) | 257 (154) a |
| Echocardiography | |||||
| Cardiac and atrial dimensions | |||||
| Cardiothoracic ratio | −0.03 (0.7) | 2.34 (0.6) a | 0.56 (0.7) | 3.07 (0.7) a | 0.23 (0.8) |
| Left atrial/cardiac ratio | 0.15 (0.05) | 0.15 (0.03) | 0.15 (0.04) | 0.15 (0.05) | 0.19 (0.04) a |
| Ventricle dimensions and areas | |||||
| Left ventricular basal transverse diameter z-score | −0.02 (0.6) | 0.08 (0.4) | −0.76 (0.6) a | 0.22 (0.6) | −1.03 (0.6) a |
| Left ventricular longitudinal diameter z-score | 0.06 (0.5) | 0.17 (0.6) | −0.75 (0.6) a | 0.23 (0.9) | −0.86 (0.5) a |
| Left sphericity index | 1.81 (0.2) | 1.73 (0.2) a | 1.81 (0.2) | 1.72 (0.2) a | 1.79 (0.4) |
| Left end-diastolic ventricle area z-score | 0.03 (0.5) | 0.12 (0.6) | −0.49 (0.5) a | 0.19 (0.3) | −0.55 (0.8) a |
| Left relative wall thickness | 0.72 (0.2) | 0.86 (0.2) a | 0.72 (0.2) | 0.90 (0.3) a | 0.73 (0.2) |
| Myocardial wall thicknesses | |||||
| Left end-diastolic ventricle wall thickness z-score | −0.06 (0.6) | 2.43 (0.8) a | −0.13 (2.1) | 2.31 (1.02) a | −0.22 (1.6) |
| Systolic function | |||||
| TAPSE z-score | −0.04 (0.6) | −0.51 (0.7) a | −0.43 (0.5) | −0.56 (0.6) a | −0.58 (0.7) a |
| MAPSE z-score | 0.03 (0.4) | −0.23 (0.6) a | −0.35 (0.7) a | −0.49 (0.5) a | −0.72 (0.8) a |
| Isovolumetric contraction time z-score | 0.01 (0.3) | 1.77 (0.5) a | −0.09 (0.5) | 1.84 (0.7) a | 0.04 (0.4) |
| Ejection time z-score | −0.01 (0.8) | 0.36 (0.4) | −0.07 (0.7) | 0.27 (2.1) | −0.12 (0.5) |
| Myocardial performance index z-score | −0.01 (0.5) | 1.27 (0.7) a | 0.16 (0.7) | 1.45 (0.4) a | −0.15 (0.8) |
| Left ejection fraction z-score | 0.03 (0.5) | −0.06 (0.6) | 0.11 (2.13) | −0.56 (1.6) | 0.22 (0.6) |
| Right FAC z-score | 0.00 (0.4) | −0.34 (0.7) a | −0.25 (0.6) | −0.23 (0.7) a | −0.4 (0.6) |
| Volumes | |||||
| Combined cardiac output z-score | 0.02 (0.7) | −0.05 (0.7) | −1.14 (0.8) a | −0.09 (0.6) | −1.66 (0.9) a |
| Cardiac index mL/min/kg | 400 (120) | 386 (117) | 304 (113) a | 393 (123) | 300 (118) a |
| Diastolic function | |||||
| Isovolumetric relaxation time z-score | 0.05 (0.6) | 1.63 (0.9) a | 0.09 (0.5) | 1.72 (0.6) a | 0.1 (0.4) |
a P <.05 compared with controls. P value adjusted for estimated fetal weight at the time of ultrasound.
| Characteristic | Controls (n=50) | TTTS I-II | TTTS III-IV | ||
|---|---|---|---|---|---|
| Recipients (n=25) | Donors (n=20) | Recipients (n=22) | Donors (n=20) | ||
| Gestational age at scan, wk | 29.2 (3.4) | 29.3 (2.3) | 29.3 (4.9) | 29.5 (2.4) | 29.4 (3.7) |
| Estimated fetal weight, g | 1342 (350) | 1219 (420) | 1052 (353) a | 1284 (376) | 1018 (310) a |
| Echocardiography | |||||
| Cardiac and atrial dimensions | |||||
| Cardiothoracic ratio z-score | 0.05 (0.4) | 0.88 (1.3) a | −0.03 (1.6) | 1.1 (1.04) a | 0.17 (1.5) |
| Left atrial/cardiac ratio | 0.16 (0.03) | 0.15 (0.04) | 0.16 (0.08) | 0.16 (0.02) | 0.17 (0.06) a |
| Ventricles dimensions and areas | |||||
| Left ventricular basal transverse diameter z-score | 0.05 (0.5) | 0.1 (0.9) | −0.7 (0.5) a | 0.2 (0.8) | −1.56 (0.6) a |
| Left ventricular longitudinal diameter, mm | 0.05 (0.8) | 0.03 (0.6) | −0.92 (0.9) a | 0.06 (0.5) | −1.25 (0.7) a |
| Left sphericity index | 1.85 (0.3) | 1.86 (0.3) | 1.83 (0.2) | 1.88 (0.36) | 1.86 (0.25) |
| Left end-diastolic ventricle area, cm 2 | −0.04 (0.5) | − 0.14 (0.3) | −1.55 (0.7) a | −0.24 (0.8) | −1.80 (0.8) a |
| Left relative wall thickness | 0.72 (0.13) | 0.78 (0.12) a | 0.67 (0.12) | 0.80 (0.11) a | 0.76 (0.14) |
| Myocardial wall thicknesses | |||||
| Left end-diastolic ventricle wall thickness z-score | − 0.01 (0.4) | 0.79 (0.7) a | −0.17 (0.4) | 1.24 (0.8) a | −0.28 (0.9) |
| Systolic function | |||||
| TAPSE z-score | 0.06 (0.7) | − 0.45 (0.8) a | −0.75 (0.4) a | −0.97 (0.4) a | −1.95 (0.9) a |
| MAPSE z-score | 0.06 (0.6) | − 0.73 (0.6) a | −0.83 (0.6) a | −1.4 (0.6) a | −0.88 (0.9) a |
| Isovolumetric contraction time z-score | − 0.08 (0.7) | 0.13 (0.7) | −0.2 (0.7) | 0.12 (0.8) | −0.25 (0.6) |
| Ejection time z-score | 0.07 (0.5) | − 0.23 (0.5) | −0.1 (0.7) | −0.07 (0.6) | −0.15 (0.5) |
| Myocardial performance index z-score | 0.04 (0.6) | 0.94 (0.8) a | 0.31 (1) | 1.1 (0.4) a | 0.34 (0.5) |
| Right FAC z-score | − 0.01 (0.4) | − 0.48 (0.7) a | −0.43 (0.7) | −0.54 (0.9) a | −0.56 (0.9) |
| Volumes | |||||
| Combined cardiac output z-score | 0.00 (0.8) | 1.01 (0.9) a | −0.65 (0.8) a | 1.67 (0.6) a | −1.11 (0.7) a |
| Cardiac index mL/min/kg | 398 (113) | 460 (134) a | 348 (124) a | 540 (135) a | 342 (115) a |
| Diastolic function | |||||
| Isovolumetric relaxation time z-score | − 0.06 (0.5) | 0.56 (0.8) a | −0.18 (0.4) | 0.67 (0.7) a | −0.16 (0.9) |
a P <.05 compared with controls. P value adjusted for estimated fetal weight at the time of ultrasound.
Recipients
Overall, regarding morphometric parameters, recipients presented larger cardiothoracic and bilateral atrial areas associated with hypertrophic ventricular walls and the septum than controls and donors (stages III-IV cardiothoracic ratio z-score: 3.22 [0.7] vs controls: −0.03 [0.5], P <.001; stages III-IV left end-diastolic ventricle wall thickness: 2.77 [0.6] vs controls: −0.03 [0.7]; P <.001). It is important to emphasize that the cardiothoracic ratio and the ventricular wall thickness were above the 2 z-scores.
In addition, they exhibited more globular ventricles through the decreased bilateral sphericity index and a concentric hypertrophy associated with the increased relative wall thickness.
The longitudinal function is reduced and global cardiac parameters reflected in the reduced right FAC (stages III-IV right FAC: −1.3 [0.7] vs controls: 0.00 [0.6]; P <.05), right SF, bilateral stroke volumes, and, consequently, the combined cardiac output. Moreover, recipients showed longer isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and increased MPI, which were the only functional parameters over the 2 z-scores. The recipient’s diastolic dysfunction is also reflected in the higher estimated ventricular filling pressures.
The postsurgical echocardiographic evaluation showed improved recipients’ cardiac function and smaller atrial areas compared with their presurgical echocardiographic status. After surgery, atrial areas were normalized; there was a significant improvement in the systolic function, especially in the right heart, as observed through the increase in the right FAC and right SF.
Evaluation at 28 to 32 weeks of gestation showed that the recipients’ cardiac hypertrophy persisted with a larger cardiothoracic ratio, thicker ventricular free walls and septum, and a consequent increase in bilateral relative wall thickness. However, the ventricles’ geometry did not differ from controls in terms of sphericity index, and there were no differences in the atrial areas. Most of the functional parameters were normalized compared with controls, with the exceptions of longitudinal motion (stages III-IV TAPSE z-score: −0.97 [0.4] vs controls: 0.06 [0.7]; P <.05) and the right FAC.
Donors
At the time of TTTS diagnosis, donors did not present significant differences in cardiothoracic ratio and myocardial wall thickness compared with uncomplicated MCDA fetuses. However, donors exhibited smaller ventricular diameters and areas adjusted by EFW. Regarding functional parameters, donors in all stages presented impaired systolic function exhibiting decreased longitudinal motion and decreased stroke volumes. Moreover, donors presented increased MPI, largely because of shorter ejection time at all stages (stages III-IV ejection time z-score: −1.67 [0.6] vs controls: 0.0 [0.7]; P <.001).
After surgery, the decreased longitudinal function persisted; however, ejection time and MPI were normalized compared with controls. Moreover, because of volume/pressure restitution after LPCV, donors presented a downturn in umbilical arterial pulsatility index, an increment in bilateral stroke volumes and cardiac outputs, and subsequently an increased pulsatility in the ductus venosus and appearance of tricuspid regurgitation. In addition, these changes are associated with the significant increase in the bilateral atrial area to heart area ratio; nonetheless, ventricle areas and dimensions continued to be smaller than those of controls.
In the third trimester, the echocardiographic assessment showed no differences in relative cardiac size; however, it displayed smaller bilateral ventricular diameters and areas. Atrial area to heart ratios were normalized. Longitudinal function persisted altered and the reduced stroke volumes and bilateral cardiac output (stages III-IV cardiac index: 342 [115] mL/min/kg vs controls: 398 [124] mL/min/kg; P <.05).
Assessment at 6 to 12 months of age
Controls were taller and heavier than recipients and donors, and they had an increased BMI. Cardiovascular assessment at 6 to 12 months of age is displayed in Table 6 . Error bar direction graphs showing the prenatal and postnatal evolution of functional and morphometric parameters in recipients are presented in Figures 2 , 3 , and 4 . Donors’ error bar direction graphs exhibiting the longitudinal functional evolution are shown in Figure 5 .
| Characteristic | Controls (n=50) | TTTS I-II | TTTS III-IV | ||
|---|---|---|---|---|---|
| Recipients (n=25) | Donors (n=20) | Recipients (n=22) | Donors (n=20) | ||
| Age at evaluation, mo | 8.2 | 8.1 | 8.1 | 8.0 | 8.0 |
| Height, cm | 70 (7) | 66 (5) a | 66 (6) a | 65 (6) a | 66 (7) a |
| Weight, kg | 8.6 (3.4) | 7.5 (2.8) a | 7.7 (2.2) a | 7.3 (2) a | 7.5 (1.3) a |
| BMI | 18 (2) | 17 (1) a | 17 (1) a | 17 (1) a | 17 (1) a |
| Systolic blood pressure, mm Hg | 102 (19.5) | 100 (17) | 100 (15) | 100 (14) | 103 (12) |
| Diastolic blood pressure, mm Hg | 55 (22) | 55 (21) | 54 (4) | 56 (18) | 55 (10) |
| Cardiac morphometry | |||||
| LV end-diastolic diameter z-score | −0.03 (0.7) | 1.16 (0.6) a | −0.25 (0.8) | 1.2 (0.9) a | −0.27 (0.9) |
| LV end-systolic diameter z-score | 0.00 (0.8) | 1.2 (0.9) a | 0.10 (0.9) | 1.44 (0.9) a | 0.21 (0.9) |
| IVS end-diastolic thickness z-score | 0.36 (0.9) | 1.51 (0.9) a | 0.36 (0.7) | 1.62 (0.8) a | 0.25 (0.7) |
| IVS end-systole thickness z-score | 0.44 (0.6) | 1.41 (0.9) a | 0.45 (1.1) | 1.54 (0.9) a | 0.51 (0.8) |
| LV end-diastolic posterior wall z-score | 0.17 (0.8) | 0.91 (0.7) a | −0.26 (0.9) | 1.12 (0.9) a | −0.38 (0.8) |
| LV end-systolic posterior wall z-score | 0.1 (0.9) | 0.97 (0.9) a | −0.08 (0.7) | 1.17 (0.8) a | −0.1 (0.04) |
| LV mass/body surface area | 41.4 (9.7) | 67.4 (9.1) a | 47.9 (7.3) | 68.47 (5.2) a | 59.2 (3) |
| Left relative wall thickness | 0.30 (0.02) | 0.33 (0.02) a | 0.30 (0.01) | 0.35 (0.02) a | 0.30 (0.01) |
| LV end-diastolic volume z-score | −0.03 (0.8) | 0.93 (0.9) a | −0.03 (0.6) | 1.17 (0.9) a | −0.06 (0.8) |
| Systolic function | |||||
| LV ejection fraction, % | 69.50 (4.4) | 72.1 (4.1) | 72.94 (4.9) | 74 (2.5) a | 71 (5) |
| LV shortening fraction, % | 36.36 (3.4) | 38.46 (3.3) | 39.13 (3.8) | 40 (2.1) a | 38 (4.2) |
| Tricuspid ring displacement z-score | 0.23 (0.9) | −0.23 (0.9) a | −0.67 (0.8) a | −1.02 (1) a | −0.76 (0.6) a |
| Mitral S’ z-score | −0.03 (0.6) | −0.05 (0.9) | 0.04 (1) | 0.01 (0.9) | 0.08 (0.7) |
| Diastolic function | |||||
| Mitral E z-score | 0.21 (0.6) | −0.23 (0.5) | 0.03 (0.8) | −0.32 (0.9) | 0.00 (0.4) |
| Mitral A z-score | 0.12 (0.7) | 0.23 (0.7) | −0.44 (0.7) | 0.48 (0.9) | −0.12 (0.8) |
| Mitral E/A ratio z-score | −0.23 (0.6) | −0.44 (0.7) | −0.34 (0.6) | −0.55 (0.8) | −0.56 (0.9) |
| Mitral E’ (lateral) z-score | −0.16 (0.8) | −0.29 (0.8) | −0.67 (0.7) | −0.33 (1.3) | −0.34 (0.6) |
| Mitral A’ z-score | 0.17 (0.5) | 0.23 (0.6) | 0.27 (0.8) | 0.32 (0.9) | 0.27 (0.9) |
| Mitral (lateral) E/E’ ratio z-score | 0.04 (0.7) | 0.00 (0.8) | −0.03 (0.6) | 0.14 (0.3) | −0.14 (0.6) |
| Isovolumetric relaxation time z-score | −0.05 (0.7) | 0.42 (0.7) a | −0.04 (0.7) | 0.62 (0.9) a | −0.15 (0.8) |
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