Elsevier

Placenta

Volume 30, Issue 5, May 2009, Pages 379-390
Placenta

Current topic
The Basic and Clinical Science of Twin–Twin Transfusion Syndrome

https://doi.org/10.1016/j.placenta.2009.02.005Get rights and content

Abstract

Twin–twin transfusion syndrome (TTTS) is a fascinating condition in which fetuses of identical genotype adopt discordant cardiovascular phenotypes, secondary to unbalanced placental inter-twin transfusion. Flow along the primary units of inter-twin transfusion, unidirectional arteriovenous anastomoses, can be as high as litres/day each, and TTTS develops when the placenta has insufficient compensatory counter-transfusional anastomoses. The initial phenotype reflects dysvolaemia, with added contributions from uteroplacental insufficiency in the donor, and raised afterload with diastolic dysfunction secondary to discordant endothelin and placentally derived renin–angiotensin system effectors in the recipient. Endoscopic laser ablation of placental anastomoses has become the primary treatment modality, supported by a randomised trial showing improved survival and short but not long-term neurological morbidity. Its uptake has facilitated comparative pre- and post-laser studies, which provide considerable insight into the pathophysiology. Despite the therapeutic advance, placental laser remains associated with a 25% incidence of fetal death within a week, and a 10% risk each of recurrence and twin anaemia/polycythaemia sequence due to residual anastomoses. In Stage I, high rates of non-progression with more conservative management have resulted in therapeutic equipoise as to whether laser is indicated primarily or only for progressive disease. The challenge ahead lies in improving double intact survival rates, which in addition to randomised trials will require technical advances, better understanding of the circulatory pathophysiology and more sophisticated surveillance tools.

Introduction

Despite major therapeutic advances in the decade since our last comprehensive review [1], twin–twin transfusion syndrome (TTTS) still accounts for around half of all perinatal deaths associated with monochorionic (MC) multiple pregnancy [2]. Its challenging management and enigmatic pathophysiology have been the subject of intense research effort over the last 5 years, spawning 341 of the 879 papers on TTTS listed in Pubmed to Dec 31, 2008.

On the upside, we now have reasonable understanding of the placental vascular signatures that result in transfusional imbalance [3], [4], [5], and the resultant fetal haemodynamic adaptions [6], [7]. Endoscopic ablation of anastomoses has become the only invasive fetal therapy proven by randomised controlled trial to improve perinatal survival [8], and is now available in many leading centres [9]. Much physiological insight has come from post-laser ablative studies [10], [11], with prevention of altered compliance in genetically concordant phenotypically discordant survivors the first evidence in humans that cardiovascular programming may be reversible [12], [13]. Finally, increasingly sized cohort studies point to overlap with discordant growth restriction [14], with twin anaemia polycythaemia sequence (TAPS) [15], and with unexpected fetal death [16], [17].

On the downside, the relative inaccessibility of the previable placenta and lack of an animal model pose major barriers to understanding the genesis and developmental plasticity of vascular anastomoses [18]. Clinically, predictive tests have poor utility [19], [20], while persistent and reverse transfusion are increasingly recognised complications of laser therapy [21], [22]. After the failure of a second randomised trial of laser in TTTS [23], there remains doubt over the optimal treatment of Stage 1 disease [24]. The fact that at best only half TTTS pregnancies treated with laser have two neurologically intact survivors [9], [25], [26] illustrates the magnitude of the therapeutic challenge ahead.

To begin, TTTS affects 10–20% of MC diamniotic (MCDA) twins, resulting in discordant amniotic fluid volume, with hypovolaemia and oliguric oligohydramnios in the donor and hypervolaemia and polyuric polyhydramnios in the recipient. If severe, the donor may manifest with growth restriction, hypoxaemia and absent/reverse end diastolic frequencies (AREDF) in the umbilical artery, while the recipient may progress to cardiomegaly, AREDF in the ductus venosus and hydrops. This review uses both the conventional diagnostic criteria (deepest pool <2 and >8 cm in donor and recipient MC diamniotic sacs respectively) [27] and notwithstanding its limitations [28], [29], the Quintero staging system [27].

Section snippets

Functional anastomotic anatomy

Injection studies show that almost all MC placentae have chorionic plate anastomoses between the two fetal circulations [3], [5], [15], [30], and consistent with this tracer studies support inter-twin transfusion being a near-ubiquitous event [31], [32]. There are two types. Superficial anastomoses lie on the chorionic plate, and are true connections between pairs of arteries (AA) or veins (VV) from the different circulations. In contrast, deep connections between a chorionic artery and a

Dysvolaemia

The characteristic discordance in amniotic fluid volume is attributed to hypervolaemia and hypovolaemia, leading respectively to polyuria in the recipient and oliguria in the donor. The resultant increase in the recipient's atrial pressure is thought to mediate an increase in cardiac atrial natriuretic peptide (ANP) synthesis, which increases glomerular filtration rate and decreases tubular re-absorption resulting in polyuria. ANP and brain natriuretic peptide (BNP) are elevated in recipient

Prediction

Three markers have been proposed to predict TTTS: increased nuchal translucency (NT), membrane folding, and absence of an AA anastomosis.

The incidence of increased NT in euploid MC twins is increased (8% of fetuses, 13% of pregnancies) compared to singletons, with nuchal oedema in the recipient a manifestation of early haemodynamic compromise [95]. However, the low sensitivity to predict TTTS of only 33% along with a 28% positive predictive value results in a modest positive likelihood ratio

Technique

Laser coagulation of the vascular anastomoses addresses the underlying cause of TTTS through a single intervention. The equipment requirements are detailed elsewhere [142], but typically a 2.0-mm endoscope is inserted percutaneously under regional or neuroleptanalgesia under operative asepsis, ultrasound guidance and antibiotic prophylaxis, with a 400–600-μm fibre introduced down the operating channel, connected to an Nd:YAG or diode laser source. A variety of techniques have been advocated to

Equipoise

Although the Eurofetus trial concluded that laser was the more effective treatment for all stages of TTTS, the treatment of early stage disease remains controversial [167]. Essentially, laser-related fetal losses [135] need to be balanced against relatively favourable outcomes with more conservative approaches [24]. Only 11 Stage I patients were included in the Eurofetus trial, and the results showing a higher rate of any survival in early stage disease were based on pooled analysis with a much

Conclusions

This review details the considerable advances in the basic and clinical science underpinning TTTS in recent years. Although the commonest anastomotic signature remains unbalanced AV anastomoses without arterioarterial anastomoses, the large volume flows and specific mid-gestational susceptibility window suggests dynamic and elastic haemodynamic compensatory mechanisms, in which discordant placental vs. renal renin–angiotensin mediators have been implicated. Clinically laser ablation has

Acknowledgements

We are grateful for program funding in both Brisbane and London from the Richard and Jack Wiseman Trust.

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