L. Y. Wee

Influence of twin-twin transfusion syndrome on fetal cardiovascular structure and function: prospective case–control study of 136 monochorionic twin pregnancies

Objective: To test the hypothesis that identical twins show no inter-twin differences in cardiovascular structure or physiology in fetal life unless there has been twin-twin transfusion syndrome. Design: Unselected prospective case–control observational study of fetoplacental haemodynamics including echocardiography at a median of 24 (16.7 to 32.3) weeks, with postnatal confirmation of congenital heart disease or normality. Setting: Fetal medicine unit. Patients: 136 women with monochorionic diamniotic twin pregnancies, of which 47 fetal twin pairs (35%) had twin-twin transfusion syndrome. Results: There were no haemodynamic differences between the bigger fetus (twin 1) and the smaller co-twin (twin 2) in uncomplicated monochorionic diamniotic pairs. In twin-twin transfusion syndrome, recipient fetuses had increased aortic and pulmonary velocities compared with their donor co-twins (mean (SD): 0.73 (0.23) m/s and 0.63 (0.14) m/s), respectively, v 0.53 (0.16) m/s and 0.48 (0.10) m/s in donor twins; p = 0.003 (aortic) and < 0.0001 (pulmonary)), and also in comparison with twin 1 and twin 2. The overall prevalence of congenital heart disease was increased above that in singletons (3.8% v 0.56%; 6.9% in twin-twin transfusion v 2.3% in uncomplicated monochorionic diamniotic twins), with inter-twin discordance for defects. The prevalence in recipient twins was 11.9% (p = 0.014 v uncomplicated control twins). Conclusions: Fetuses with an identical genome but no circulatory imbalance have similar cardiovascular physiology but discordant phenotypic expression of congenital heart disease. The high prevalence of congenital heart disease in monochorionic diamniotic twins merits detailed fetal echocardiography.

Validation of the Quintero staging system for twin-twin transfusion syndrome

OBJECTIVE To validate an established staging system for twin‐twin transfusion syndrome. METHODS Prospective observational study in a tertiary referral fetal medicine center of 52 consecutive cases of twin‐twin transfusion syndrome. Each pregnancy was assessed longitudinally for a variety of prognostic factors including fetal biometry, amniotic fluid volume, arterial and venous Doppler sonogram abnormalities, and the presence of hydrops. Data were used to determine stage at diagnosis and first treatment, and worst stage throughout pregnancy. Perinatal outcome was assessed by stage. Management comprised serial amnioreduction, septostomy, selective reduction, or delivery, alone or in combination. RESULTS Median gestation at presentation and first treatment were both 21 weeks (range 14–34 and 15–34), and at delivery it was 29 weeks (range 16–40). Sixty‐three percent of pregnancies (33 of 52) were at least stage III at presentation. Forty‐five percent of pregnancies (22 of 49) progressed to a more advanced stage. Overall survival was 47% (47 of 100), with no difference between donor and recipient fetuses (40% [20 of 50] versus 54% [27 of 50] [χ2 P < .5]). Survival rates were 58% (15 of 26), 60% (six of ten), 42% (20 of 48), 43% (six of 14), and 0% (none of two) for stages I–V, respectively, with no significant influence of stage at presentation on survival. Survival was poorer where stage increased, versus decreased (27% [12 of 44] versus 94% [17 of 18] χ2 P < .001). Kaplan‐Meier survival curves indicated that staging at presentation identified pregnancies at greater risk of earlier rather than later gestational perinatal loss. CONCLUSION The Quintero staging system did not distinguish good from bad outcome at presentation, and thus should be used with caution in guiding initial management of twin‐twin transfusion syndrome. However, prognosis was influenced by a change in stage, and pregnancies progressing to higher stage disease were at increased risk of earlier perinatal loss. Staging may thus be more useful in monitoring disease progression.

Non-invasive fetal electrocardiography in singleton and multiple pregnancies

Objectives To document the duration of fetal cardiac time intervals in uncomplicated singleton pregnancies using a novel non‐invasive fetal electrocardiography (fECG) system and to demonstrate this techniques ability to acquire recordings in twin and triplet pregnancies.

Transmitted arterio-arterial anastomosis waveforms causing cyclically intermittent absent/reversed end-diastolic umbilical artery flow in monochorionic twins.

OBJECTIVES To characterize the phenomenon of retrograde transmission of arterio-arterial anastomosis (AAA) interference patterns on umbilical artery (UA) waveform by (a) documenting the periodicity, (b) correlation with in vivo and in vitro demonstration of AAAs and (c) reproducing these patterns by computer modelling. METHODS Monochorionic twins (MC) twins underwent placental and umbilical Doppler studies. AAAs were sought by pulse wave Doppler of their bi-directional interference pattern and confirmed by postnatal injection studies. The periodicity of transmitted patterns in the UA was determined. Determinants of the transmitted patterns were ascertained by computer modelling of physiological and fetal variables. RESULTS Among 83 prospectively studied MC twin pregnancies; a transmitted pattern was observed in 6 (7 per cent) patients for 15-114 days. This was found in 20 per cent (6/30) of smaller MC twins discordant for growth restriction but in no appropriately grown twins. It was only observed in association with AAAs validated both in vivo and in ex vivo. Computer modelling demonstrated that this pattern could be reproduced by summating end diastolic flow with a high pulsatility index in the UA in the presence of a large AAA. Consistent with this, MC twins with a transmitted pattern had larger AAAs (median diameter 4.3 mm interquartile range 4.1-5.2) compared to MC twins discordant for intrauterine growth restriction (2.1 mm interquartile range 1.5 to 2.8) (P<0.05) without a transmitted pattern. Perinatal mortality was similar in the fetuses with and without transmitted patterns (0/12 vs. 2/48 P=0.7).

Doppler for artery-artery anastomosis and stage-independent survival in twin-twin transfusion.

OBJECTIVE: Treatment selection in twin–twin transfusion syndrome is increasingly determined by disease severity. We investigated whether detection of arterio-arterial anastomoses predicts perinatal survival. METHODS: An artery–artery anastomosis was sought by Doppler and disease stage was determined in 105 cases of twin–twin transfusion syndrome at presentation, first treatment, and worst stage. Outcome measures were perinatal, double, and any (1 or more babies) survival rates. RESULTS: After exclusion of 10 noninformative pregnancies, perinatal, double, and any survival rates were 61%, 44%, and 77%, respectively. When an anastomosis was detected at each of the 3 time points, perinatal and double survival rates were higher than when one was not (at first treatment, perinatal survival 83% versus 53%, respectively, P = .003; double survival 78% versus 33%, P < .001). Perinatal and double survival (P ≤ .01) were poorer with more advanced stage, but any survival rates were not influenced by stage or anastomosis detection. Multiple logistic regression demonstrated that anastomosis detection at treatment increased the chance of perinatal (odds ratio [OR] 5.1, 95% confidence interval [CI] 1.6, 15.9) and double survival (OR 19.3, 95% CI 2.7, 138), independently of stage. For stages I–III at treatment, anastomosis detection predicted better perinatal (100% versus 63%, 100% versus 59%, and 83% versus 44%, respectively) and double survival rates (100% versus 52%, 100% versus 46%, and 78% versus 26%). Stage III, with anastomoses detected, had better perinatal (83% versus 63%) and double survival (78% versus 52%) than did stage I without detection. CONCLUSION: Antenatal detection of artery-to-artery anastomosis predicts higher perinatal and double survival in twin–twin transfusion syndrome, independently of disease stage. LEVEL OF EVIDENCE: II-3

The Placenta Contributes to Activation of the Renin Angiotensin System in Twin–Twin Transfusion Syndrome

The renin-angiotensin system (RAS) in twin-twin transfusion syndrome (TTTS) is up-regulated in the donor fetuss kidneys, but down-regulated in the recipients. Ultrasonographic and echocardiographic features suggest that the recipient is also exposed to RAS components. In this study we investigated the role and origin of RAS components in the recipient fetus. Monochorionic diamniotic (MCDA) pregnancies were recruited from a tertiary fetal medicine service. Cord blood was collected from MCDA twins (TTTS and control non-TTTS) at delivery for renin and angiotensin II immunoassays. Placental tissue was flash-frozen for mRNA and protein expression or formalin-fixed for immunohistochemistry. Archival placenta and kidney samples were used for immunohistochemistry and in-situ hybridization. Plasma renin levels were elevated (p<0.05) in recipients (median 201 pg/ml, range 54-315 pg/ml) and donors (125 pg/ml, 25-296) with TTTS compared to controls (2.5 pg/ml, 1.1-1.5 pg/ml). The same was found with angiotensin II with high levels in both recipients (300.5 pg/ml, 86.1-488 pg/ml) and donors (239 pg/ml, 76.6-422) compared to controls (169.5 pg/ml, 89-220 pg/ml, p<0.05). Renin mRNA expression, and protein appeared qualitatively higher in the placental territory of the recipient compared to that of the donor and non-TTTS controls. We conclude that both fetuses in TTTS are exposed to high levels of RAS components; these appear to be produced from different sites, namely the kidney of the donor, and the placenta of the recipient. Given the markedly different phenotypes in the genetically identical fetuses with TTTS, we suggest that the source of RAS components may influence their clinical manifestations.

Increased latency of absent end‐diastolic flow in the umbilical artery of monochorionic twin fetuses

To determine if absent end‐diastolic flow (AEDF) in the umbilical artery (UA) has a longer latency in monochorionic (MC) twin fetuses compared to singleton or dichorionic twin (DC) fetuses.

Re: Intra-amniotic Doppler measurement of blood flow in placental vascular anastomoses in twin-twin transfusion syndrome.

Nakata et al. recently reported a novel, invasive intraamniotic Doppler technique to measure blood flow rates in arteriovenous anastomoses (AVAs) in twin–twin transfusion syndrome (TTTS) of up to 25 mL/min or 36 L/day1. Velocities of this magnitude underpin previous reports that AVAs are detectable non-invasively by transabdominal ultrasound2. However, we are concerned that the biological implausibility of the huge total intertwin net flows they derive appears to have escaped the attention of both the authors and the reviewers. The net transfusional blood flow of up to 11.6 mL/min that they report equates to nearly 17 L per day. No adult would survive this depletion or addition to its circulation for more than a few hours, let alone a midtrimester fetus. For instance, we estimate that at 20 weeks’ gestation, when fetal placental volume is approximately 40 mL, such a net loss of blood volume would take only 3 min to result in fetal exsanguination. In contrast, we have recently derived more biologically plausible net flows (0.004 mL/min at 28 weeks or 60 mL/day) with data obtained non-invasively by color Doppler insonation of superficial anastomoses3. Nakata et al. fail to acknowledge that their assessment of flow is instantaneous and therefore unreliable if flow rates fluctuate, as seems likely. Indeed, support for temporal variation comes from their somewhat counter-intuitive result showing that the gradient of net flow in TTTS is from recipient to donor. There are several possibilities for the authors’ seemingly erroneous calculation of net flow. Firstly, they made no attempt to exclude false-negative anastomoses that they may have failed to identify at endoscopy. Da Paepe et al.4 recently showed that on average more than two AVAs are missed per laser procedure. In addition, our group has shown using placental cast studies that in only half the shared cotyledons in monochorionic placentae are AVAs characterized by cotermination of an artery and the vein on the chorionic plate surface5. Instead, large numbers of deep anastomoses lie beneath the chorionic plate and therefore cannot be visualized directly by chorionic plate inspection. Second, although the authors imply that their technique is more accurate than transabdominal Doppler, they made no attempt to validate their new technique or establish its reproducibility, such as with flow phantoms, or in larger in-vivo vessels like the umbilical artery with known flow rates, or by ex-vivo perfusion experiments. Nor do they acknowledge the limitations of vessel diameter measurement using color Doppler, or of the equations used to derive blood flow. Small inaccuracies in diameter will be exaggerated by calculations dependent on the square of the radius to calculate blood flow velocity. Finally, patients with anterior placentae were selected in this study. This may be an additional explanation for missed anastomoses, as the same group have previously described the difficulties with visualization in such cases6. We congratulate the authors on their creativity, but suggest that both the technique and endoscopic visualization will need validation before useful pathophysiological inferences can be drawn from such results. While appreciating that this was only a preliminary report in correspondence, we do not feel this exonerates the Journal from peer review, nor the authors from acknowledging the limitations of their method.

Variable umbilical artery end‐diastolic frequency is associated with arterio–arterial anastomosis

We read with interest the report by Kush et al.1 describing the phenomenon of variable umbilical artery (UA) enddiastolic flow in monochorionic (MC) twins. Kush et al. attribute this waveform pattern to the presence of a velamentous insertion based on their single case but provide no mechanism whereby velamentous umbilical arterial vessels would lead to intermittent alteration in the waveform pattern. They also refer to an earlier report since discredited suggesting that velamentous insertion occurs more frequently in twin-twin transfusion syndrome (TTTS). We recently completed a detailed study of 90 MC placentae where the frequency of velamentous cord insertion in TTTS was similar to that in non-TTTS MC controls (53% vs. 52% – Taylor et al.2). The phenomenon of cyclical end-diastolic frequencies in UA waveforms in MC twins has been described previously3,4. Our group has documented an association between cyclical interference patterns in the UA Doppler waveforms and arterio–arterial anastomosis (AAA), and verified their physiological basis by computer modeling. This interference pattern cycles through present, then absent and often reversed end-diastolic frequencies before end-diastolic frequencies return (Figure 1). The periodicity of the cyclical pattern is equal to the period of the AAA, which is a function of the difference in two fetal heart rates4. In our series, this cyclical pattern occurred in a fifth of growth restricted MC twins with an AAA detected in vivo, but never in their large/appropriately grown co-twins nor in MC twins without an AAA detected in vivo. We reproduced this pattern in a computer

OC227b: Doppler detection of arterio‐arterial anastomosis predicts survival outcome independent of Quintero stage in TTTS

Objectives: 1) To assess the accuracy of fetal echocardiography in multiple pregnancy, and 2) To evaluate the type of congenital heart disease (CHD) and of extracardiac anomalies detected in 36 cases of multiple pregnancy. Method: We analysed a population of 248 pregnancies (546 fetuses, 39 with CHD). Diagnostic accuracy was calculated for fetal echocardiography. In fetuses with CHD, the following variables were analysed: chorionicity, gestational age at diagnosis, type of CHD, associated chromosomal and extracardiac abnormalities, fetoneonatal outcome. Results: In this series, sensitivity was 88.8%, specificity 99.8%, PPV 97.1% and NPV 99.1%. There were 4 FP and 1 FN cases. The association with aneuploidy was 9.3% (3/32). The spectrum of CHD was similar to that seen in singleton during the same period of time. Of note, that 8/32 (25.0%) fetuses with CHD were recipients from monochorionic pregnancies complicated by TTTS. As for the outcome, 21 (65.6%) neonates survived and 11 (34.4%) died prior to (9) or after surgery (2). Conclusions: Fetal echocardiography is clearly feasible also in multiple pregnancy without particular difficulties, at least for twins. In triplets and quadruplets, fetal crowding makes things a great deal more difficult. The association with aneuploidy is lower than expected, possibly due to the low incidence of extracardiac anomalies in this series and to the relatively small number of cases. As to the outcome, low birthweight coupled with CHD seem to be an important bad prognostic indicator, be it for growth restriction or simply prematurity.