Treatment of twin–twin transfusion syndrome

Abstract

Twin–twin transfusion syndrome is characterized by unequal blood exchange from the donor twin to the recipient co-twin through placental vascular anastomoses. Treatment of twin–twin transfusion syndrome consists of serial amnioreduction, septostomy, laser photocoagulation of placental vessels and umbilical cord occlusion of the apparently sick twin. Amnioreduction reduces maternal discomfort due to polyhydramnios and improves fetal circulation by reducing amniotic fluid pressure on the placenta. Septostomy equalizes amniotic fluid pressure between the two gestational sacs. Laser therapy interrupts intertwin blood shunting and restores two independent circulations. Umbilical cord occlusion is offered when signs of imminent death are present, such as hydrops and cardiac failure. Laser therapy is associated with increased neonatal survival rates and lower risk of adverse outcomes compared with other treatments.

Keywords::

• amnioreduction
• laser therapy
• neonatal outcomes
• septostomy
• twin–twin transfusion syndrome
• umbilical cord occlusion

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Release date: 12 October 2012; Expiration date: 12 October 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Distinguish ultrasound findings characteristic of TTTS

• • Evaluate interventions to reduce amniotic volume in cases of TTTS

• • Assess the efficacy and safety of laser therapy for TTTS

• • Compare techniques of selective infanticide in cases of TTTS

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

Author and Credentials

A Cristina Rossi, MD

Department of Obstetrics and Gynecology, University of Bari, Bari, Italy.

Disclosure: A Cristina Rossi, MD, has disclosed no relevant financial relationships.

Twin–twin transfusion syndrome (TTTS) is a condition unique to monochorionic pregnancies, in which the twins have their circulations connected by placental blood vessels. The syndrome occurs in approximately 10% of monochorionic pregnancies and results from unequal blood exchange from one twin (donor) to the co-twin (recipient) through placental vascular anastomoses [1–3]. Three types of placental anastomoses that connect intertwin circulation can be detected in all monochorionic placentas: arterioarterial anastomoses, venovenous anastomoses and arteriovenous anastomoses [4]. The first type seems to have a protective role, because it balances blood shunting between the two fetuses. Conversely, arteriovenous capillary bed generates TTTS because of unbalanced flow from the donor to the recipient’s circulation. Arteriovenous anastomoses from the recipient to the donor can also be present and compensate shunting from arteriovenous anastomoses from the donor to the recipient [5]. However, when this compensation fails to balance intertwin blood shunting, TTTS develops. Why and when unequal blood exchange occurs is still unknown. Furthermore, in twins affected with TTTS, the renin–angiotensin system is compromised, with overfunction in the donor and downregulation in the recipient [6]. Discordant renin–angiotensin systems can be observed as early as the first trimester together with structural abnormalities of fetal kidneys – that is, hypoplastic kidneys in the donor and hypertrophic kidneys in the recipient. Because the vascular connections are responsible for hypovolemia in the donor and hypervolemia in the recipient, and because renal function is impaired in both twins, oligohydramnios develops in the donor’s sac and polyhydramnios develops in the recipient’s sac. Therefore, the diagnosis of TTTS comprises sonographic detection of oligohydramnios (maximal vertical pocket ≤2 cm) and polyhydramnios (maximal vertical pocket ≥8 cm) in the donor and recipient sacs, respectively [7].

Fetal death of one twin places the surviving twin at increased risk of mortality and morbidity, because of disseminated intravascular coagulation due to the passage of thromboplastic material from the dead fetus to the surviving fetus through placental vascular anastomoses. According to another theory, blood pressure reduces acutely in the dying twin and leads to exsanguination of the survivor to the dying twin through placental vascular anastomoses [8].

The treatment of monochorionic pregnancies complicated with TTTS is based on the physiopathological features previously described. In particular, prenatal therapy consists of amniodrainage, septostomy, laser photocoagulation of placental vascular anastomoses and selective feticide by umbilical cord occlusion.

Amnioreduction

Polyhydramnios of the recipient fetus can reach extreme levels that may lead to preterm labor, premature rupture of membrane and maternal respiratory compromise. In addition, amniotic pressure increases and may alter placental perfusion, resulting in further hypovolemia and oligo/anuria in the donor fetus. Amnioreduction, the percutaneous removal of large volumes of amniotic fluid from the recipient’s sac, may prevent these complications. Amnioreduction as a treatment of TTTS has the advantage of being a technically simple procedure, does not require sophisticated technology and specialized centers, and can be performed without administration of anesthetics. The main disadvantage of amnioreduction is that it is a symptomatic therapy that ameliorates maternal discomfort and normalizes amniotic fluid pressure, but does not remove the etiology of TTTS. Because placental anastomoses remain patent, polyhydramnios relapses and amniodrainage must be performed periodically. Serial amnioreduction is associated with an overall survival rate ranging from 38 to 81% [9]. Neonatal death has been reported in 14–39% of twins, and cerebral anomalies affect 18–83% of cases [9]. The wide variance of the incidence of perinatal outcomes following serial amnioreduction for TTTS might depend on the number of amnioreductive procedures and gestational age at delivery.

Another severe complication of serial amnioreduction is that in case of intrauterine demise of one fetus, amnioreduction does not prevent severe injury to the surviving co-twin, because thromboembolic materials from the dead to the surviving fetus or acute transfusion from the surviving to the dead fetus may still occur through patent vascular anastomoses. These complications result in intrauterine demise or cerebral handicaps.

Septostomy

Septostomy is the intentional rupture of the intertwin septum by ultrasound guidance and is aimed at balancing the amniotic fluid pressure in the two sacs leading to a correction of the placental circulation, mainly in the donor twin’s vessels. In addition, filling the amniotic sac of the donor twin decreases cord compression, improves fetal hemodynamics and increases urine production by the donor twin [10]. Similarly, in serial amnioreduction, septostomy has the disadvantage of removing the clinical sign (polyhydramnios) but not the etiology of TTTS (placental anastomoses). Adverse effects of septostomy are similar to those described for serial amnioreduction, such as preterm labor and premature rupture of membranes. An additional risk is represented by the creation of a monoamniotic pregnancy that can be associated with cord entanglement. The incidence of survival rate following septostomy for TTTS varies widely from 36 [10] to 83% [11]. A possible explanation might be the differing severity of TTTS at the time of intervention. Although there is a trend toward increasing gestational age at delivery with septostomy compared with amnioreduction [12], a randomized trial of amnioreduction versus septostomy showed that overall perinatal survival was similar between the two groups, and septostomy offered the advantage of requiring a single procedure [13].

Because of lower survival rates and higher risk of neonatal morbidity compared with laser therapy, septostomy is not commonly performed as treatment of TTTS.

Laser therapy

The rationale behind laser treatment for TTTS involves the interruption of the placental vascular anastomoses through which intertwin blood exchange occurs. Arteries are identified endoscopically by visualization of corresponding vein crossover and their darker color. Laser therapy for TTTS has gradually evolved. It was first described by De Lia et al., who described photocoagulated vessels that could be responsible for intertwin transfusion at the vascular equator. How the vascular equator was identified was not clearly described [14]. In 1995 Ville et al. modified the technique by targeting all the vessels that crossed the membrane dividing the two amniotic sacs [15]. The assumption of this surgery was that all the vessels crossing the dividing membrane were placental anastomoses [15]. In 1998 Quintero et al. observed that many placental vessels could cross the dividing membrane without creating anastomoses between the circulations of the two twins [16]. Furthermore, the dividing membrane could shift toward the donor sac due to the polyhydramnios in the recipient’s sac, and this displacement could lead to photocoagulation of normal vessels of the donor circulation and increase the risk of morbidity and mortality of the donor fetus [16]. Therefore, a selective technique was developed that identifies the terminal end of the artery from one of the two fetus to which a vein returning to the other fetus corresponds [16]. The alternate origin of the two vessels can also be detected by following their paths up to the umbilical cords. Selective ablation of placental anastomoses is associated with better outcomes compared with nonselective surgery, because the former does not occlude normal vessels but is limited to the vascular anastomoses [16]. Selective laser therapy can be safely performed under local anesthesia, which is associated with a lower incidence of intraoperative maternal hypotension compared with general anesthesia [17]. Therefore, local anesthesia allows constant uteroplacental blood flow during surgery [17]. The overall survival rate of twins treated with laser therapy for TTTS ranges from 57 to 77% [9].

Compared with serial amnioreduction, laser therapy has the advantage of definitively removing the etiology, and not just the symptoms, of TTTS and ‘dichorionizes’ the placenta by restoring two independent circulations. The disadvantages are that laser therapy requires highly specialized centers and professional skills, is performed under anesthesia and is a more invasive technique compared with amnioreduction. The milestone for the assessment of the efficacy of laser therapy compared with amnioreduction is represented by the randomized clinical trial by Senat et al., which demonstrated that perinatal outcomes improve after laser therapy [18].

A meta-analysis compared amnioreduction and laser therapy, and showed that laser therapy is associated with better perinatal outcomes (Table 1) [9]. Nonetheless, cerebral impairment is not fully prevented by laser therapy. Periventricular hemorrhagic infarction, hemhorragic injury and ischemic white matter injury have been reported in neonates treated with laser therapy. A very recent review, which pooled 895 laser-treated twins, assessed that the incidence of neurologic morbidity is approximately 6% at birth and 11% at follow-up, and equally affects donors and recipients [19]. The most frequent damage is represented by cerebral palsy (39%), of which hemiplegia accounted for 41%, quadriplegia for 33% and diplegia for 16% [19]. Cerebral morbidity also manifests as psychomotor delay (22%), mental delay (22%), sensorial deficits (3%) and less frequently as talipes equines, microcephaly, speech maldevelopment, ventriculomegaly, mulyicistic encephalomalacia, strabismus, nystagmus and amblyopia [19]. In approximately 24% of twins, more than one neurodevelopmental anomaly can be detected [19]. The highest incidence of neurologic impairment is usually detected at 11 months of age (22%) and decreases to 9% at 36 months [19]. The review also showed that the intrauterine demise of one twin is not a risk factor for neurologic morbidity of the surviving co-twin [19]. This finding indicates that laser therapy interrupts intertwin blood shunting and results in a ‘functional dichorionic’ twin gestation. Consequently, the surviving twin is protected from transfusion of thromboembolic material or massive exsanguination that may result from the intrauterine death of its co-twin. This is the main advantage of laser therapy compared with amnioreduction, in which placental anastomoses remain patent. In other words, serial amnioreduction removes the symptoms of TTTS – that is polyhydramnios – whereas laser therapy removes the etiology of TTTS.

Fetal and maternal complications secondary to laser therapy have been observed. Iatrogenic premature rupture of membranes accounts for 27% and results in a mean gestational age at birth as early as 31 weeks [20]. The survival rate of TTTS complicated with iatrogenic premature rupture of membranes is 66% [20]. Inadvertent septostomy may occur in 7% of cases and is associated with a substantially increased risk of adverse perinatal outcomes [21]. Other severe complications include intraoperative bleeding, pulmonary edema, abruption placenta and chorioamnionitis, which occur in 17% of surgeries [22].

Selective feticide by umbilical cord occlusion

Selective feticide for TTTS is offered when sonographic examination shows signs of severe damage to one of the two fetus, such as severe hydrops and cardiac failure. Occasionally, parents may opt for umbilical cord occlusion as primary treatment for TTTS.

In high-order multiple pregnancies, selective feticide is performed by fetal potassium chloride injection if dichorionic placenta is demonstrated. In monochorionic twins, this procedure cannot be performed, because the healthy fetus would be at very high risk of embolization and potassium transfer through placental vascular anastomoses [23]. Conversely, bipolar cord coagulation, radiofrequency ablation and cord occlusion by ligation or photocoagulation of the umbilical vessels allow interruption of blood flow to the selected fetus while avoiding lethal complications to the co-twin.

The optimal technique has not yet been established [24]. Bipolar cord coagulation requires a short operating time and is associated with a low risk of cord entanglement and amniotic band syndrome, but may be complicated by cord bleeding and limited by the cord size. Radiofrequency ablation is a very efficacious technique, which induces temperature changes by high-frequency alternating currents resulting in cord coagulation. However, thermal damage may cause fetal hemorrhage, amniotic bands and maternal thermal injuries.

Selective feticide by umbilical cord occlusion as treatment for TTTS is associated with survival rates of the nontargeted twin equal to 80% [24]. When stratified for type of surgery, the highest survival rate is observed after bipolar cord coagulation (83%), followed by radiofrequency ablation (60%) and umbilical cord ligation (50%) [24]. In addition, when selective feticide is performed after 18 weeks, the survival rate of the healthy twin is higher than after selective feticide performed before 18 weeks (87 and 75%, respectively) [24]. In the case of termination of donors, 86% of co-recipients survive, which is similar to the donor survival rate (84%) after termination of the corecipients [24].

Conclusion

The optimal treatment for TTTS is laser therapy, because it is associated with better neonatal outcomes compared with both serial amnioreduction and septostomy. Laser therapy allows the interruption of placental anastomoses, resulting in two independent circulations of the two twins. This leads to two important considerations. First, intrauterine death of one twin does not compromise the health status of the surviving co-twin. Second, the photocoagulation of placental anastomoses is a definitive treatment and does not require additional interventions, since in only a minority of anastomoses cases remain patent but can be successfully photocoagulated by a second procedure. Umbilical cord occlusion is a successful procedure, but should be reserved to cases in which one of the two twins appears severely sick, such as in the presence of severe hydrops or cardiac failure.

Expert commentary

TTTS is a severe complication of monochorionic pregnancies. Both original articles and reviews show that laser photocoagulation of placental anastomoses should be considered as the optimal treatment, since it ‘dichorionizes’ the single placenta into two different circulations. This results in two important factors: first, it corrects the hypovolemia and hypervolemia that affect the donor and recipient, respectively, as demonstrated by Doppler studies in which normalization of blood flow in the umbilical artery and middle cerebral artery is observed after laser treatment. Second, intrauterine demise of one fetus does not represent a risk factor for adverse outcomes in the surviving co-twin.

The role of laser therapy for TTTS in Quintero stage I is under debate. Stage I represents the mildest form of TTTS (visualization of donor’s bladder), and recent literature shows that the natural history of stage I varies widely, since spontaneous resolution, progression or stable disease have been observed in TTTS stage I. Randomized studies comparing expectant management with laser therapy are necessary in order to establish what should be the first choice treatment in TTTS stage I.

Five-year view

There is evidence that operator skill and experience in performing laser therapy for TTTS has improved over time. In addition, the advances in ultrasound tools and the development of small trocars diameters have widely contributed to increase survival rates of neonates affected with TTTS. Further improvement in training and technologies is expected in the next five years.

Table 1. Comparison between laser therapy and amnioreduction.

Neonatal outcomes	Laser therapy (%)	Serial amnioreduction (%)	OR (95% CI)
Overall survival rate	66	47	3.00 (1.42–6.30)
Neonatal death	8	25	0.24 (0.15–0.40)
Cerebral anomalies	13	29	0.20 (0.13–0.34)

Significant difference if 95% CI does not encompass 1.

OR: Odds ratio.

Data taken from [9].

Key issues

• • Twin–twin transfusion syndrome is a severe complication of monochorionic pregnancies.

• • The optimal treatment is laser therapy, at least for the advanced forms of the syndrome.

• • The role of serial amnioreduction and septostomy is limited due to the superiority of laser therapy.

• • Laser therapy has the advantage of removing the etiology rather than the symptoms of twin–twin transfusion syndrome.

• • Maternal and fetal complications of laser therapy occur in a minority of cases.

• • Selective feticide should be offered only in cases of imminent death of the apparently sick twin or in cases of sonographic detection of cerebral hemorrhage in one twin, for which termination of the pregnancy is advocated.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Treatment of twin–twin transfusion syndrome

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1.You are seeing a 33-year-old woman with a twin pregnancy. Ultrasound reveals that she has a monochorionic pregnancy. Which of the following ultrasound findings in the donor fetus is characteristic of twin–twin transfusion syndrome (TTTS)?

• □ A Hypertrophic kidneys and polyhydramnios

• □ B Hypoplastic kidneys and polyhydramnios

• □ C Hypoplastic kidneys and oligohydramnios

• □ D Hypertrophic kidneys and oligohydramnios

2. The patient has evidence of TTTS. What should you consider regarding procedures to reduce amniotic fluid volume?

• □ A Septostomy remains a standard of care for TTTS

• □ B Amnioreduction can be performed with minimal anesthesia

• □ C The perinatal survival rate following amnioreduction is 75% to 80%, with little variation between studies

• □ D Amnioreduction improves perinatal survival vs septostomy

3. What should you consider regarding the possibility of laser therapy for this patient?

• □ A Even selective laser therapy requires general anesthesia

• □ B The perinatal survival rate of twins treated with laser therapy is 57% to 77%

• □ C Laser therapy is similar to amnioreduction in terms of perinatal outcomes

• □ D Neurologic complications occur in less than 1% of infants treated with laser therapy

4. 4. Treatment fails to prevent severe hydrops fetalis in one of the twins, while the other twin appears healthy. What should you consider regarding selective feticide at this point?

• □ A Injected potassium chloride is the optimal technique

• □ B Bipolar cord coagulation is the optimal technique

• □ C Radiofrequency ablation is the optimal technique

• □ D Selective feticide is associated with a survival rate of 80% for the non-targeted twin