Twin-Twin Transfusion Syndrome (TTTS): May 2017

Friday, May 19, 2017

Serial Amniocentesis

TTTS. Serial Amniocentesis

Amniocentesis is the standard screening technique for fetal anemia, because amniotic fluid contains hemolytic products excreted from the fetal kidneys and lungs, including bilirubin.

Amniocentesis (also referred to as amniotic fluid test or AFT) is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, and also for sex determination, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amniotic sac surrounding a developing fetus, and then the fetal DNA is examined for genetic abnormalities.

The most common reason to have an "amnio" is to determine whether a baby has certain genetic disorders or a chromosomal abnormality, such as Down syndrome. Amniocentesis (or another procedure, called chorionic villus sampling (CVS)) can diagnose these problems in the womb. Amniocentesis is performed when a woman is between 14 and 16 weeks gestation.

Women who choose to have this test are primarily those at increased risk for genetic and chromosomal problems, in part because the test is invasive and carries a small risk of miscarriage. This process can be used for prenatal sex discernment and hence this procedure has legal restrictions in some countries. Amniocentesis was first introduced by American obstetrician Fritz Friedrich Fuchs and Danish gastroenterologist Polv Riis in 1956 for fetal sex determination and up to mid 1970s amniocentesis were done 'blind‘.

TTTS. Septostomy

The rationale on the use of septostomy or dividingmembrane amniorrhexis for the treatment of TTTS was to equilibrate the amniotic pressures on both sides of the membrane.10,11 Prior to its proposal, a difference in amniotic fluid pressures in the two sacs was never demonstrated.

On the contrary, Quintero and others showed that, in fact, the pressure in both sacs is similar.12,13 Notwithstanding, a randomized controlled trial was carried out to compare septostomy versus amnioreduction.14 The study was terminated at the planned interim analysis stage after 73 women were enrolled.

TTTS. Medical Treatment

Medical treatment of TTTS has included only isolated case reports involving the use of digoxin3–5 or indomethacin.6–8 The rationale for the use of digoxin is to treat a recipient twin in heart failure.

Relatively high maternal serum levels of digoxin must be achieved in order to reach therapeutic levels in TTTS, as the mean feto–maternal gradient is 0.56.9 Fetal levels are also directly related to GA.

Treatment of twin–twin transfusion syndrome: an evidence-based analysis

Management of twin–twin transfusion syndrome (TTTS) has encompassed a wide spectrum of options, including expectant management, medical therapy, and surgery, as well as pregnancy termination.

Over the past few years, significant emphasis has been given to the development of clinical practice guidelines that are derived from evidence-based medicine.

Twin to Twin Transfusion Syndrome. Results

Between July 1997 and June 2002, 252 patients with the diagnosis of TTTS underwent surgical treatment at our center. UCO was performed on 36 (14.3%) of these patients. Ten cases were excluded from the analysis because they had undergone secondary UCO after an attempted SLPCV (technical success rate for TTTS 216/226, or 95.5%).

One additional case was excluded because the ligated cord was that of a recipient twin that had died shortly before surgery. Thus, 25 cases of TTTS underwent primary UCO. Six (24%) had cord occlusion of the donor fetus (donor group) and 19 (76%) of the recipient fetus (recipient group). Six fetuses had the following discordant fetal malformations: 2 had neural tube defects (both donors), 1 had body-stalk anomaly (donor), 1 had pulmonary atresia (recipient), 1 had anencephaly (recipient), and 1 had intracranial hemorrhage (recipient).

Twin-Twin Transfusion Syndrome. Surgical technique

The two methods of cord occlusion performed were umbilical cord ligation (UCL) or umbilical cord photocoagulation (UCP). UCL was performed via a 3.5 mm trocar inserted percutaneously into the amniotic cavity via 1–2 mm skin incision under continuous ultrasound guidance and general or local anesthesia.

The cord of the target fetus was identified endoscopically with a 2.7–3.3 mm diagnostic or operating endoscope (Richard Wolf, Inc., Vernon Hills, IL, USA). A 3-0 Vicryl suture that had been previously threaded through a custom-designed knot-pusher was passed down the working channel of the endoscope with a semi-automatic grasper (Cook Ob/ Gyn, Spencer, IN, USA), or through a second port, and was laid underneath the target umbilical cord.

TTTS. Methods

Standard sonographic diagnostic criteria for TTTS included polyhydramnios in the recipient twin (maximum vertical pocket [MVP] ?8 cm), oligohydramnios in the donor twin (MVP ?2 cm), single placenta, same gender, and thin-dividing membrane with absent ? or twin-peak sign.

Each case was prospectively classified using the Quintero staging system,15 as described in Chapter 7. Primary UCO was offered if there was (1) presence of a lethal discordant fetal anomaly, or (2) stage III/IV in a patient who elected this modality.

Umbilical cord occlusion in twin–twin transfusion syndrome

As discussed in Chapter 9, the surgical treatment of twin–twin transfusion syndrome (TTTS) involves primarily laser obliteration of the anastomoses responsible for the syndrome. Occasionally, however, selective feticide of one of the fetuses must be contemplated.

Indications for selective feticide in TTTS include a discordant anomalous twin or failed attempted laser therapy. The former are classified as being primary, the latter as being secondary selective feticides. Occasionally, patients may choose primary selective feticide after counseling, in accordance with their own personal opinions regarding potential outcomes.

Selective laser photocoagulation of communicating vessels in monoamniotic twins

Contrary to common belief, TTTS does occur in monoamniotic twins and is thought to occur in approximately 10% of monochorionic twins. Since monoamniotic twins represent approximately 1% of all monochorionic twins, TTTS would occur in 0.1% of monochorionic twins, or approximately 1:24 000 pregnancies.

Monoamniotic twins may have any of the above placental distribution patterns, but, in particular, may be more prone to have extensive vascular anastomoses and a circular placental vascular pattern. In addition, the distance between the cords may be exceedingly short, with large AA or VV anastomoses. Cord entanglement may also be present, placing the fetuses at an increased risk of in-utero demise from this complication.

Selective laser photocoagulation of communicating vessels in triplet gestations

Triplet or higher-order multiple gestations may also develop TTTS, provided that a monochorionic placentation exists. In the case of triplets, pregnancies may be either dichorionic or monochorionic. SLPCV in dichorionic triplets differs little from that of twins, other than the unaffected ‘singleton’ may interfere with trocar access to the amniotic cavity of the recipient twin.

In monochorionic triplets, one of three combinations may exist: one recipient–two donors, one donor–two recipients, and one donor–one recipient–one unaffected. Because vascular anastomoses will typically be present between all three fetuses, a seemingly unaffected triplet may serve as a go-between fetus between the other two.

Supraselective laser photocoagulation of communicating vessels

SLPCV results in a functional or surgical dichorionization of a monochorionic placenta. Indeed, as a result of obliterating all vascular anastomoses, the remaining placental cotyledons are perfused individually by each twin (individual placental territory, or IPT).

All shared cotyledons, with the exception of three-vessel or four-vessel cotyledons, are rendered non-functional. Survival of any one twin after SLPCV depends, at least partially, on whether the remaining IPT is enough to sustain in-utero life (see Chapter 5)

Selective laser photocoagulation of communicating vessels in patients with an anterior placenta

An anterior placenta presents additional technical challenges in patients undergoing percutaneous SLPCV for severe TTTS. The challenges consist of finding a placenta-free area in the anterior uterine wall through which the trocar can be inserted and being able to assess all vascular communications from that entry site. Finding a placenta-free area in the anterior wall may be difficult, particularly if the placenta is widely extended.

In addition, anterior placentas may also ‘wrap around’ the lateral walls, precluding free access to the amniotic cavity. Approaches to the treatment of patients with anterior placentas that cannot be addressed with a straight operating endoscope have included performing a wide laparotomy with forward flipping of the uterus and entry into the amniotic cavity from the posterior wall (De Lia, pers comm); performing a mini-laparotomy and inserting a bent cannula;23 use of flexible-steerable operating endoscopes. In 2001 we published on two techniques to address patients with anterior placentas.

TTTS. Trocar assistance

The relationship between the trocar and the endoscope varies from manufacturer to manufacturer. Most of the endoscopes available for operative fetoscopy follow the hysteroscopy design, in which the tip of the endoscope is flushed with the tip of the trocar and the back end of the endoscope locks with the trocar sheath.

In our design, the trocar and endoscope are independent of each other, with the endoscope being purposely 4 cm longer than the trocar length. Fluid leakage is prevented not by a locking mechanism, but rather, by a rubber cap and a check-flow valve within the trocar. With our specific trocar and endoscopic design, we have developed the concept of trocar assistance.

Anastomoses within the sac of the donor twin

Vascular communications may be found within the sac of the donor twin in approximately one-thrid of patients with TTTS.

In these patients, the anastomoses may take one of several forms:

• Terminal end visible. In these patients, the terminal end of the vessels and, thus, the actual site of the anastomosis, can be seen. Branching prior to the anastomosis may or may not exist, but does not interfere with access to the terminal end.

• Terminal end not visible. In these patients, the terminal end of the vessel is not visible, whether because of extensive branching of the recipient vasculature within the sac of the donor, or because of donor interference.

TTTS. Removal of the trocar

Once the desired level of amniotic fluid volume in the sac of the recipient twin is reached, the suction–irrigation trumpet is removed and the patient is alerted to the removal of the trocar. Trocar removal is monitored with ultrasound to detect bleeding from the anterior uterine wall or membrane detachment.

If neither occurs, the incision is covered with a band-aid, steri-strips or dermabond to conclude the surgery. Bleeding from the anterior uterine wall may occur at any point during surgery, but most commonly after removal of the trocar. Bleeding is typically short-lived, and can usually be contained with external digital pressure over the incision site of approximately 5 minutes.

TTTS. Post-laser amniodrainage

Surprisingly, the topic of how much fluid should be removed during a therapeutic amniocentesis has received relatively little attention.18 Descriptive terms such as ‘aggressive’ or ‘radical’ have been used to describe the philosophical objective of the procedure.

Objectively, goals range from decreasing the amniotic fluid volume to the level of oligohydramnios or to low-normal levels, using either MVP (maximum vertical pocket) or AFI (amniotic fluid index) as the measuring parameter.19–22 Most centers advocate reducing the MVP to a level of 5–6 cm.

Lasering of AV anastomoses

AV anastomoses can be interrupted by lasering the artery, the vein, or both. In theory, lasering of the vein still allows for blood to be lost into the cotyledon, and may be responsible for development of intraoperative fetal anemia. Therefore, when possible, we prefer to laser the artery first. Most placentas will have both AVDRs and AVRDs.

Whenever possible, we prefer to laser AVDRs first followed by AVRDs, as this may allow for an intraoperative transfusion of the donor twin (sequential technique, or SQLPCV). Lasering of superficial anastomoses Lasering of AA and VV anastomoses requires that the surgeon decide where, along the path of the vessel, the interruption needs to be made (Figure 9.11a and b).

Selective laser photocoagulation of communicating vessels

There are three steps in performing selective laser photocoagulation of communicating vessels (SLPCV). The first step is a diagnostic one, which consists of the identification of all of the anastomoses, differentiating them from individually perfused areas of the placenta (diagnostic fetoscopy step).

The second step consists in the actual lasering of the anastomoses. The third step involves reviewing all of the lasered anastomoses and relasering if necessary, as well as endoscopic review of any other important aspects of the amniotic cavity or fetuses.

TTTS. Trocar entry

In standard laparoscopy, the trocar insertion sites have been extensively worked out to avoid injury to the superficial epigastric vessels. In contrast, the site of entry into the amniotic cavity of the recipient twin will vary from patient to patient.

The site of entry is chosen after careful preoperative mapping (Chapter 7) to avoid injury to the dividing membrane or the placenta. Injury to the superficial epigastric vessels is avoided by placing the trocar either at the midline or 8 cm lateral from the midline.15 Power angio Doppler insonation of the myometrium under the proposed site of entry may disclose important vessels that need to be avoided (Figure 9.9).

Patient positioning, prepping, and draping

Chapter 15 discusses in detail the operating room preparation of the patient. The patient is placed in the decubitus position. A left or right lateral tilt may be required if the patient develops hypotension from caval compression. The dorsolithotomy position is chosen in selected cases to avoid an anterior placenta and if no access from the right or the left side of the patient is available. A Foley catheter is placed in the bladder. The patient is then fully prepped and draped as for any major surgery.

Anesthesia

Chapter 18 discusses in detail our experience with general and local anesthesia. Most centers today use local anesthesia in the form of 1% lidocaine without epinephrine. A 10 ml syringe with a 21-gauge 11/2 inch needle is used. The skin is infiltrated to create a wheal. The needle is then inserted under ultrasound guidance to infiltrate the tissues to the level of the uterine serosa.

Basic operating room setup

TTTS. Basic operating room setup

The operating room setup is the basic operative fetoscopy arrangement originally described by us.14 Basically, the setup involves the use of ultrasound imaging, endoscopic imaging, and a laser equipment. In the United States, the ultrasound machine is placed to the right of the patient, as most sonographers are accustomed to scanning with their right hand, facing the patient.

An endoscopic tower is also placed on the right side of the patient, more distally, to allow viewing of the surgery across the patient from the left side. An additional monitor is placed on the left side of the patient (slave monitor).

Additional slave monitors may be used to allow viewing of the procedure from any angle of the operating room, as well as a dedicated monitor for the patient. The laser machine is placed on the left side of the patient. The patient is typically placed in decubitus. Occasionally, the dorsolithotomy position is used for patients with difficult access to an anterior placenta.

TTTS. Length of instruments

Adequate length of the trocar, endoscopes, and working instruments is paramount. In addition, the relationship between trocar length and endoscope length may vary between product companies. In one system, the endoscope and trocar are flushed at the tip, with a locking mechanism at the back end to prevent loss of fluid (hysteroscopic model).

This system requires that the trocar and endoscope complex be moved back and forth within the amniotic cavity to reach the different vessels. In the endoscopes designed by Quintero (laparoscopic model), trocar length is always smaller than endoscope length. Fluid loss is prevented by a checkflow valve within the lumen of the trocar.

TTTS. Accessory instruments

Accessory ports (2 mm) and blunt probes can be particularly useful under specific circumstances. Accessory ports may be required to pass sidefiring laser fibers or blunt probes to complete surgery in some patients with anterior placentas.

Blunt probes may be used to displace the donor twin to allow visualization of vascular anastomoses that may be blocked by this fetus. Although not often used, these accessory instruments may be critical in the completion of surgery in certain patients.

TTTS. Laser source

The physical characteristics of the Nd:YAG laser make it particularly suitable for use within the amniotic cavity and for coagulation of blood vessels. The CO2 laser (wavelength 10 600 nm), which is the most commonly used laser in gynecology, is highly absorbed by water.10 Thus, it cannot be used within the amniotic fluid. In contrast, the Nd:YAG laser (wavelength 1064 nm) can transmit energy through clear fluid.

The laser is a solid crystal of yttrium–aluminum– garnet (YAG) that contains a dopant of the rare earth element of neodymium (Nd), which actually makes the light. When applied through a bare fiber, the Nd:YAG causes deep tissue coagulation. Protein coagulation of 1–2 mm can be achieved with a power of 20 watts for 1–3 seconds.

TTTS. Endoscopes

Although some endoscopes were specifically designed for fetoscopy in the 1970s, all endoscopes currently used are either custom-made or adaptations from other surgical specialties. Familiarity with technological aspects of the endoscopes is important in order to understand their capabilities and limitations.

The endoscope has two fundamental systems: a light bundle that carries light to the tip of the endoscope, and the optic pathway which carries back the image under observation. The light bundle can be located at the periphery of the scope, but several other arrangements are also possible. Transmission of the image from the object to the eyepiece can be performed in three basic ways: fiberoptics, solid rod lens, or multiple lens.

Technical Aspects. Amniotic fluid exchange

The amniotic cavity may be turbid, particularly with advancing gestational age. Visualization may be further hindered by bloody discoloration from previous procedures such as amniocenteses or cordocenteses, from intraoperative intraamniotic bleeding, or from excessive vernix.

Light transmission in these settings can be significantly compromised. To overcome this problem, we have developed techniques to exchange the amniotic fluid with Ringer’s lactate or 0.9 saline solution. One technique uses a custom-designed suction– irrigation probe or ‘trumpet’ (Figure 9.2) that is inserted through the trocar under ultrasound guidance and directed to a pocket of amniotic fluid.

Technical Aspects. The working environment: fluid or gas

Ideally, surgery within the amniotic cavity would be performed under a gas environment, as in standard laparoscopy. Indeed, visualization within gas is superior to that within fluid, both in terms of light transmission as well as in the angle of view which is reduced by 30% in water.

Working within gas would also be advantageous should bleeding in the amniotic cavity occur. Work within gas would also allow the use of electrosurgery, CO2 laser and other standard surgical techniques. Carbon dioxide is the most widely used gas in laparoscopy because it does not support combustion and dissolves readily in the patient’s blood.

Laser treatment for Twin–Twin Transfusion Syndrome

The fundamental principle behind the laser treatment of twin–twin transfusion syndrome (TTTS) consists of interrupting the vascular anastomoses that allow blood exchange between the fetuses and thus eliminating the intertwin transfusion process.

The surgical technique assumes that all placental vascular anastomoses can be identified and obliterated. Neodynium:YAG laser photocoagulation of placental vascular anastomoses was first proposed by De Lia in the late 1980s.1 The approach involved performing a limited laparotomy, placement of a purse string in the myometrium, and introduction of a trocar and endoscope to perform fetoscopy.

Efficacy of amnioreduction as a Therapy in Twin–Twin Transfusion Syndrome

Amnioreduction has been employed as a primary or adjunctive therapy in TTTS for two decades. As discussed previously, this technique does not alter the underlying pathophysiology of unbalanced vascular anastomoses in monochorionic– diamniotic twin placentation, but appears to prolong gestation by reducing intra-amniotic pressure and improving uteroplacental perfusion.

The available data on the efficacy of amnioreduction are based on two randomized controlled trials,16,35 one cohort comparative study,36 and many observational series of varying size and methodological quality.3,7–9,11,27,28,34,37–48 The initial data on outcomes for TTTS were derived from non-controlled institutional observational studies.

TTTS. Amnioreduction: Technique

Amnioreduction is a technically simple procedure, although appropriate patient selection, patient positioning, and drainage mechanisms are important to minimize procedure-related complications. The procedure may be accomplished without sophisticated technology, although there has been a recent trend in the use of vacuum-assisted devices to withdraw the amniotic fluid rather than manual techniques.

There is wide variation in the amnioreduction technique in terms of needle gauge used, the volume and rate of amniotic fluid withdrawn, and the completion MVP or amniotic fluid index (AFI). Interestingly, despite these procedural differences, the reported success rates of this technique are remarkably similar.27,28 Patient sedation with a benzodiazepine is helpful for maternal comfort and to reduce excessive fetal movement of the recipient fetus during the procedure.

Amnioreduction: Physiological Rationale

Amnioreduction, the percutaneous removal of large volumes of amniotic fluid from the sac of the recipient fetus in TTTS, was the first widely employed intervention to significantly alter the dismal perinatal prognosis of this condition.

Indeed, this technically simple procedure remains a central component of the therapeutic armamentarium of TTTS, either alone or as an adjunct to placental laser ablation techniques. The hallmark diagnostic feature of TTTS is the oligohydramnios/polyhydramnios sequence.17,18 The donor fetus is characterized by a restrictive oligohydramnios (maximum vertical pocket [MVP] ? 2 cm) secondary to hypovolemia, whereas the recipient fetus displays hypervolemic polyuric polyhydramnios (MVP ?8 cm), creating a unique sonographic portrait (Figure 8.1).

Amnioreduction therapy for twin–twin transfusion syndrome

Twin–twin transfusion syndrome (TTTS) is one of the most challenging complications of the monochorionic twinning process. Characterized by high perinatal mortality and morbidity rates, TTTS has stimulated intense research interest globally over the past two decades.

The advent of obstetric ultrasound has enabled the accurate prenatal identification of TTTS and this detection capability has facilitated potential therapeutic interventions. Additionally, the treatment modalities have been refined as knowledge of the pathophysiology of TTTS has improved.

TTTS. Ultrasound assessment of deep communications and/or superficial anastomoses

There are a few reports on the use of ultrasound to assess deep communications or superficial anastomoses.24 Most studies have been performed on patients without TTTS and anterior placentas, as color Doppler insonation of the placental parenchyma is easier in these patients.

Deep vascular communications

The presumed diagnosis of deep placental vascular communications involves color Doppler identification of an arterial vessel coming in one direction, and a venous drainage of the same cotyledon going in an opposite direction (Figure 7.17). While such approach may indeed identify deep vascular communications, it is by no means reliable.

TTTS. Estimated fetal weight and fetal weight discordance

The legacy of neonatal criteria for the diagnosis of TTTS still lingers. A 20% discordance in birthweight was to establish the diagnosis of TTTS. Prenatal ultrasound diagnosis based on specific amniotic fluid discordances, as opposed to postnatal criteria, has eliminated birthweight discordance as a criterion. Figure 7.16 shows the frequency distribution of EFW discordance as determined by ultrasound.

As can be seen, the spectrum ranges from 0 to 65%, approximately. Restriction of the definition of TTTS to only those fetuses with at least 20% discordance would disqualify approximately 31% of all TTTS patients. The reasons for the wide range of EFW discordances are not entirely clear. Intrauterine growth retardation (IUGR) may exist independently of TTTS, as a completely separate entity.

TTTS. Step Four: Preoperative Mapping

The last aspect of the ultrasound evaluation of patients with TTTS consists of an attempt to predict the location of the dividing membrane and thus the vascular equator and direction of the vascular anastomoses. We call this step preoperative mapping.

Preoperative mapping may help in choosing the point of entry into the uterus, particularly in patients with a posterior placenta. Mapping is most accurate when the donor twin is stuck, and most difficult in stage I or if a cocoon sign is present.

TTTS. Step Three: Cervical Length Assessment

The third aspect of the ultrasound evaluation of patients with TTTS involves an adequate Figure 7.10 (a) Pulsatile umbilical venous flow. (b) Pulsatile umbilical venous flow in the umbilical vein and absent end-diastolic velocity in the umbilical artery in the same view. (See also color plate section, page xxv.) assessment of the cervical length.

Because of the early gestational age at which patients would typically present, transabdominal assessment of the cervical length is usually adequate. However, we prefer to document the cervical length via transvaginal ultrasound unless there are specific contraindications for doing so.

Stage V: Intrauterine fetal demise of one or both twins (Figure 7.13)

Sub-staging

Classic vs atypical presentation

In the classic form, the bladder of the donor twin may not be visible in stages III and IV. When the bladder of the donor is visible in any of these two stages, it represents an atypical presentation. The importance of substaging may be useful in terms of explaining the pathophysiological mechanisms responsible for the different presentation as well as potentially useful in terms of prognosis.

TTTS. Stage IV: Hydrops

Stage IV is defined by the presence of ascites, pericardial or pleural effusion, and scalp or skin edema (Figure 7.12a–c). Most if not all of these ultrasound findings are subjective. However, for the purposes of follow-up, the degree of third spacing may be monitored.

Thus, the scalp may be measured at the level of the biparietal diameter as the distance from the skin to the parietal bone; pleural effusion may be measured as the transverse distance from the tip of the lung to the inner chest wall at the level of the base of the lung;

pericardial effusion may be measured at the level of the four-chamber view as the distance between the right atrium and the pericardium in diastole; ascites may be measured at the abdominal circumference level as the distance between the anterior edge of the liver and the inner abdominal wall. Skin edema may also be measured at the level of the abdominal circumference.

Staging of

Step Two: staging of Twin–Twin Transfusion Syndrome

Our current understanding of the heterogenous presentation of TTTS explains the seemingly conflicting reports of pioneer investigators regarding the role of Doppler in TTTS.9–13 Indeed, we now know that only a subgroup of TTTS patients present with abnormal Doppler findings.

Thus, Doppler studies are more important in terms of assessing disease severity rather than in defining the syndrome. TTTS is known to be a heterogeneous condition with different presentations. Variations of the syndrome include visualization or lack thereof of the bladder of the donor twin, and the presence or absence of abnormal Doppler studies or hydrops.

TTTS. Sonographic pitfalls: the cocoon sign

Because of the presence of oligohydramnios, the donor twin is usually stuck against the walls of the uterus: thus, the name ‘stuck twin.’ However, in approximately 15% of TTTS patients, the donor twin is enveloped by the dividing membrane, such that it is connected to the uterine wall by a stalk of these membranes (Figure 7.5a–c).

As a result, the donor twin, despite having anhydramnios, may not be stuck to the uterine wall. We have called this potential sonographic pitfall ‘the cocoon sign’, as the term implies.20 Thus, a non-stuck donor twin may not necessarily be better off than a stuck one.

TTTS. Definition of polyhydramnios and oligohydramnios

Polyhydramnios and oligohydramnios are defined as sonographic estimates of amniotic fluid volumes above and below the 95th percentile for gestational age, respectively. Ultrasound assessment of amniotic fluid volume has been either subjective, or semiquantitative using the maximum vertical pocket (MVP), amniotic fluid index (AFI), or the 2-dimensional pocket (2D).

The MVP is defined as the largest vertical pocket of amniotic fluid without the presence of umbilical cord or other fetal parts. The AFI is the sum of the 4 MVPs taken in each quadrant with the transducer aligned in the sagittal plane. The 2D diameter is the product of the MVP times the maximum transverse diameter in any particular quadrant.

Current ultrasound definition of twin–twin transfusion syndrome

Several important achievements have been made in the last decade in defining TTTS. First, for the reasons mentioned above, the condition requires a sonographic diagnosis.

This is important as it establishes ultrasound as the sole reliable diagnostic tool for the condition. As a corollary, the diagnosis of TTTS in patients with monochorionic twin pregnancies with an adverse pregnancy outcome or with significant size discordance between the twins but without prenatal sonographic diagnosis of TTTS lacks definite proof of the condition and may only rely on circumstantial evidence.

Ultrasound diagnosis of twin–twin transfusion syndrome

Over the years, the sonographic definition of TTTS has been particularly marred by lack of standardization. Unfortunately, such lack of standardization has resulted in the inclusion of patients without TTTS in treatment series, or even worse, to unnecessary termination of pregnancy in patients without TTTS.

Hence, the need to establish a standard sonographic approach to TTTS cannot be overemphasized. The original ultrasound reports on the diagnosis of TTTS were based on biometric discrepancies (>10 mm of either the biparietal diameter or the transverse diameter of the trunk between the twins) in addition to polyhydramnios of the larger twin.

Ultrasound assessment

Ultrasound assessment in twin–twin transfusion syndrome

The ultrasound assessment of patients with twin–twin transfusion syndrome (TTTS) can be particularly challenging. The presence of oligohydramnios in the sac of the donor twin frequently impairs adequate visualization of the fetal anatomy, fetal gender, and occasionally, adequate Doppler interrogation of the different vessels of this fetus. Polyhydramnios is typically associated with a frequently moving recipient twin, which makes the Doppler assessment of this fetus particularly difficult.

Polyhydramnios may also result in significant maternal discomfort with back pain or light-headedness in the recumbent position, hindering further the completion of the ultrasound examination. Lastly, the examination is typically done under an atmosphere of psychological tension from maternal anxiety, given the grave prognosis in most cases. Despite these limitations, a thorough and complete ultrasound examination is necessary to correctly diagnose and assess the status of patients with TTTS. The ultrasound assessment of patients with TTTS can be systematized to be performed in several steps or levels, including diagnosis, staging, cervical length, and preoperative mapping. Each of these steps will be discussed below.

TTTS. Results

From the viewpoint of pathophysiological mechanisms, our model is clear and simple (Figure 6.3). First, stages I and II TTTS develop if the net fetofetal transfusion increases at a rate in excess of the rate of increasing growth of each twin.

Then, a stuck donor twin and markedly increased colloids in the recipient follow, albeit that recipient hypertension and urine production are not yet excessive. In our model, the strongly increased colloids cause an excess transplacental fluid flow from the maternal to the recipient circulation, a consequence of using Starling’s eqn (10), which mainly exits through the bladder, causing polyhydramnios.

TTTS. Third-generation model of a hydropic recipient

In our third model,6 we simulated a sequence of events that leads to the onset and development of hydrops in the recipient twin. Three essential elements had to be added to our second model.5 The first is vasoconstrictive peptides, described as the renin–angiotensin system (RAS) mediators that reduce urine production.

The second is the limited capacity of the fetal heart to increase its cardiac output beyond normal values following abnormally increased blood pressures,23,24 leading to a state of high-output cardiac failure. The obvious third element is an interstitial fluid compartment. Table 6.1 summarizes the 10 parameters included in this model for each twin, comprising 20 first-order differential equations.

TTTS. Second-generation hemodynamic and amniotic fluid dynamics model

In our second model,5 we added amniotic fluid dynamics to our first model. We had to adapt the mechanism of fetal blood volumetric growth. We included that the growing fetus and amniotic cavity acquire fluid and nutrients from the maternal circulation to maintain the volume of the total body fluid as well as the amniotic fluid.

Fluid and nutrients are provided by the transplacental fluid flow from the maternal to the fetoplacental circulation, implying

Because the primary model parameters are the blood volume of the twins, we had to relate blood volume with total body fluid volume. We assumed the fetal blood is a constant fraction of 10% of the total body fluid:

The growth of anastomoses, placenta and fetuses, the blood volume vs blood pressure curves, the relation for net fetofetal transfusion, and the model input parameters, were all taken identical as in the first model. In eqn (9), TotalBodyFluidGrowth directly follows from eqn (7) as the difference between TransPlacent- Flow and AmnioticFluidGrowth.

TTTS. First-generation hemodynamic model

The blood volumes of the twins are the primary model parameters because the anastomoses transport blood volume from one twin to the other. Our model relates overall growth of the blood volumes of donor and recipient twins to a linear combination of their natural growth, i.e. the anticipated normal physiological growth of their blood volume, and the net fetofetal transfusion from donor to recipient, eqn (1). Here, the NetFetofetalTransf is assumed to directly affect fetal growth of both twins.

This is an approximation that neglects possible control mechanisms that try to maintain normal growth. The following two growth equations of the fetal blood volumes constitute our first-generation model:

The plus sign denotes the equation for the recipient and the minus sign for the donor.

Proposed Twin–Twin Transfusion Syndrome Etiology and Pathophysiology

The etiology of TTTS was proposed to be a consequence of the normal development of the placental anastomoses as compared to the natural growth of the fetuses. Here, because little is known about growth of anastomoses, we assumed that normal anastomotic development is that length and diameter of the anastomoses increase proportional to gestational age.

We hypothesized that anastomoses develop similarly as chorionic and umbilical vessels and available data of serial measurements show that the diameter of AA anastomoses umbilical veins as well as the length of umbilical veins and chorionic vessels – the latter considered proportional to the diameter of singleton placentas – all grow approximately proportional to gestational age (Figure 6.1). Implication is that anastomotic resistances decrease significantly during gestation, i.e. according to eqn (2) as inversely proportional to gestational age to the 3rd power.

TTTS. Anastomoses

An AVDR anastomosis connects the umbilical artery of the donor with the umbilical vein of the recipient. The AV connections occur at the capillary level within a cotyledon that receives its blood from a donor chorionic artery and drains it by a recipient chorionic vein. AVRD anastomoses, from recipient to donor, often exist next to primary AVDRs, where the AVRDs are defined as having the smaller diameter (higher resistance) compared to the primary AVDR with the largest diameter. Further,

AA or VV anastomoses directly connect chorionic arteries or veins of the two twins. In our models, the AVDR, AVRD, AA, and VV anastomoses are represented by tubes, which directly connect with the two umbilical circulations, without branches to the normal placental chorionic vessels. This is a simplification, because it is known that most if not all anastomoses have branches to the normal placental circulation of the fetuses.

Mathematical modeling of twin–twin transfusion syndrome

Twin–twin transfusion syndrome (TTTS) is a unique complication of monochorionic twin pregnancies, diagnosed by discordant amniotic fluid volume (oligo/anhydramnios–polyhydramnios sequence). Often, but not always, serious cardiovascular sequelae develop, resulting in the assessment of TTTS as having a widely variable and unpredictable clinical presentation.

TTTS is a consequence of placental anastomoses, which can be arteriovenous from donor to recipient (AVDR), arteriovenous from recipient to donor (AVRD), arterioarterial (AA), and venovenous (VV). These anastomoses allow a net fetofetal transfusion to develop from one twin (the donor) to the other (the recipient). While about 96% of all monochorionic placentas have anastomoses, only 5–10% of them develop TTTS (see Chapter 3).

Placental Histological Changes associated with Twin–Twin Transfusion Syndrome

The portion of the placenta supporting the donor fetus is usually pale. This is in stark contrast to the recipient’s placental portion, which is congested, giving an enlarged and hyperemic appearance. However, at the level of the villi, the donor has been described as having a significantly enlarged villous structure compared with that of the recipient,47 and this has been attributed to fetal edema of the donor villi (Figure 5.11).

This finding is unexpected in that fetal edema of the donor fetus is uncommon, particularly relative to the recipient twin. The enlarged villi of the donor fetus may in turn impinge on the intervillous space, thus affecting maternal perfusion. 48 This may explain the observations made by Matijevic et al, who studied blood flow in the spiral arteries of each twin’s portion of the placenta using Doppler.

TTTS. Placental Cord Insertion

The site of umbilical cord insertion into the placenta may be described as central, paracentral, marginal, or velamentous. Unlike a central or marginal umbilical cord insertion, which inserts onto the placental disk, the velamentous cord inserts into the fetal membranes (Figure 5.10).

The bare umbilical vessels, unsupported by either umbilical cord or placental tissue, then traverse the fetal membranes between the amnion and chorion before insertion into the placenta. Although relatively uncommon in singleton pregnancies, the velamentous cord insertion occurs at a significantly higher rate in multiple gestations.

TTTS. Partitioning of Placental Mass

In addition to the vascular anatomy, it is important to consider the division of the placental mass of monochorionic placentas. Monochorionic twins may not share equal masses of villous tissue; one twin may have more placental tissue for development (Figure 5.10).

This finding has several important implications regarding monochorionic twin gestations, particularly if they are complicated by TTTS. What is the role of the individual placental mass in the pathogenesis of TTTS? Is the relatively high rate of intrauterine growth restriction noted in TTTS due the unequal partitioning of the placental mass? To help answer these questions,

TTTS. Vascular Communications

Dating back to Schatz, several observers have considered the vascular anastomoses of monochorionic placentas to be an important factor in the development of TTTS. Most authorities today agree that, to some extent, TTTS arises from unbalanced exchange of blood between twins through these vascular anastomoses.

Indeed, several studies have shown that ablation of the vascular anastomoses ‘cures’ TTTS.17,18 However, if virtually all monochorionic placentas have vascular communications, why does TTTS develop in only a minority of monochorionic pregnancies? Is there a vascular arrangement that preferentially results in TTTS or is associated with a worsened outcome?

TTTS. The Monochorionic Placenta

The monochorionic twin placenta is usually shaped as a single disk (Figure 5.2). However, the chorionicity cannot be assigned by the number of placental masses (Figure 5.3).

Dichorionic placentas that are in close proximity may abut one another and become fused into a single placental mass.14 This occurs in approximately 50% of dichorionic placentas. As detailed above, a monochorionic placenta may rarely possess separate lobes that are connected together via a diminutive bridge of placental tissue.

TTTS. Zygosity

Pregnancies complicated by TTTS are, with rare exception, monozygotic twins. Monozygotic twinning results from an early (within 14 days following fertilization) embryonic ‘splitting’ of a single zygote. The cause of this division is unknown, although some have viewed it as an anomalous embryonic event.

The timing of the division determines both the chorionicity and amnionicity.7 Division prior to the differentiation of the chorion results in the development of a dichorionic–diamniotic twin gestation; this occurs in approximately 30% of monozygotic twins.

Placental pathology and twin–twin transfusion syndrome

Twin–twin transfusion syndrome (TTTS) was initially characterized by Friedrich Schatz in the late 1800s. This body of work included a case of a monochorionic twin pregnancy that was complicated by marked discordance of infant size at birth.1–5 The larger twin was noted to be edematous and found to have micturated frequently prior to death at 12 hours of age, while the smaller co-twin never urinated and died at 53 hours of age with an empty bladder.

From detailed study of monochorionic placentas, Schatz suggested that anastomotic vessels linked the circulations of monochorionic twins. The presence of these vascular anastomoses served as a conduit for the unbalanced exchange of blood between the twins, thus setting up the circumstances for the development of TTTS. To better understand the etiology and management of TTTS, a detailed understanding of the placenta is required. The aim of this chapter is to review placental anatomy and related pathophysiology as it pertains to TTTS.

TTTS. Mathematical Modeling

Animal models of monochorionic multiple pregnancies are lacking, so mathematical modeling has become an interesting way of studying the pathophysiology of TTTS. The first model36 was based on two circulations in which a communication was produced at 28 weeks of pregnancy, reproducing the oligo/polyhydramnios sequence.

An important pathophysiological consideration is the timing on the development of TTTS relative to existence of the vascular anastomoses. Since TTTS develops in the midtrimester, despite the existence of vascular anastomoses since the beginning of the pregnancy. Later mathematical models suggested that the growth of the vessels diminish the vascular resistance faster than the growth of the fetus, which in turn the existent anastomoses into functional low resistance anastomoses. 37 The models are explained in detail in Chapter 6.

TTTS. Doppler

Doppler studies in TTTS were first reported in 20 consecutive cases in 1995.32 This cross-sectional study investigated the circulatory profile of the donor and recipient fetuses in 20 pregnancies with twin–twin transfusion syndrome presenting with acute polyhydramnios at 17–27 (mean 22) weeks’ gestation.

Doppler investigations of the arterial vessels and ductus venosus, inferior vena cava, right hepatic vein, tricuspid, and mitral ventricular inflow were performed in both fetuses. The most significant findings on the arterial side were an increased mean umbilical artery pulsatility index and a decreased mean value for aortic blood flow velocity in both groups of fetuses.

Ultrasound Staging of Twin–Twin Transfusion Syndrome

TTTS staging was introduced by Quintero et al in 1999. This is based on ultrasound features:

• stage 1 – oligo/polyhydramnios sequence only with bladder visualized in the donor twin

• stage 2 – bladder not visualized in the donor twin

• stage 3 – critically abnormal Dopplers (absent or reversed diastolic flow) in the donor umbilical artery, pulsitile venous or reverse flow in the ductus venosus

• stage 4 – hydrops in either twin

• stage 5 – demise of one or both twins.

A retrospective study of 50 TTTS cases treated by amnioreduction in Australia27 between 1993 and 2002, classified patients into stages at presentation. Overall, 22% of the cases improved after one amnioreduction, 40% remained with the same stage, and 38% progressed. It was found that the less severe TTTS was at presentation, the higher the chance to improve.

TTTS. Evidence from Fetal blood sampling.

The neonatal criterion of a difference in 5 g/dl of hemoglobin has shown to be unsuitable in utero, because of its lack of correlation with the ultrasonographic criteria and because neonatal cases select those TTTS cases with better outcome. Bruner and Rosemond18 found a difference of more than 5 g/dl by cordocentesis in only 1 of 6 cases with TTTS.

This study aimed to demonstrate donor–recipient passage of blood by a positive Kleihauer–Betke test in the recipient after in-utero tranfusion of the donor with adult O Rh? red cells. In 6 cases in which the procedure could be performed,

TTTS. Histological evidence

An interesting study on placental histology was performed in 1998.17 Tertiary villi were studied and the number of muscular arteries was counted in a subset of 9 consecutive TTTS diagnosed by ultrasound, with 20% growth discordance and oligo–polyhydramnios sequence. The placenta near the cord insertion of the donor and the recipient was studied blinded for the pathologist. They found significantly less muscular arteries in the donors (5.81 ± 0.55 vs 6.66 ± 0.24; p = 0.017).

Concomittantly, the umbilical artery S/D Doppler index was higher in the donors than in the recipients. In a previous publication of the same cases, they found that 66% of the pairs had feto–fetal transfusion, and only 25% of them had anemia/ polycythemia.

In-vivo studies

The description of placental vascular anastomoses from fetoscopies during laser photocoagulation of the chorionic plate may be used to study the placental architecture. This method is sensitive because of the endoscopic magnification of the image and is controlled because the placental surface remains with a white scar at the coagulation point.

The problem is that technically difficult fetoscopies as anterior placentas or turbid amniotic fluid may give false negative for anastomoses detection. De Lia et al14 described ablating 8–10 communicating vessels per placenta in TTTS.

Placenta. Twin–Twin Transfusion Syndrome

The normal fetoplacental circulation consists of two arteries and one vein, which divide progressively in the chorionic plate (fetal surface of the placenta), and irrigate each cotyledon in a separate way. This means that normal vascularization of the placentas may be clearly recognized by the naked eye, until it reaches the corresponding cotyledon.

All monochorionic placentas have vascular communications between the cords,5 which was demonstrated in 278 placentas from twin pregnancies. Monochorionic placentas always have vascular communications, in comparison with dichorionic fused placentas. Despite this finding, TTTS only occurs in 15% of monochorionic pregnancies. The pattern of the anastomoses is therefore determinant in the occurrence of TTTS.

Twin–Twin Transfusion Syndrome.The case Definition problem

Before the use of ultrasound, TTTS was diagnosed by a 20% discordance in the weights and at least 5 g/dl difference in the hemoglobin concentration at birth of two twins of the same sex.3 These criteria were left aside because they were not always possible to demonstrate antenatally by ultrasound and because it is frequent in diamniotic twins as much as in monochorionic twins. Besides, these were used for surviving twins but not in cases of double- or single-fetal demise, which were more possibly affected by severe TTTS.

With the development of ultrasound, new antenatal findings were correlated to adverse outcome. The polyhydramnios/oligohydramnios sequence has been found to be the condition with one of the highest mortalities in obstetrics, with 90% mortality without treatment. Recently, growth discordance with abnormal umbilical Doppler has been considered a new indication for laser photocoagulation of anastomoses on the chorionic plate.

Evidence on physiopathology

The twin–twin transfusion syndrome (TTTS) (Figure 4.1) occurs in 15% of monochorionic– diamniotic pregnancies,1 with a high perinatal mortality rate.2 These are morphologically normal fetuses, in which the vascular communications in the placenta are thought to be responsible for the development of the disease.

Besides the primary phenomenon, the disease may lead to disruptive lesions in both twins. This chapter will review the evidence for the development of the disease, its complications, and implications in therapeutical approaches. The chapter focuses at defining the clinical problem, the histopathology correlation of the clinical condition, and the ultrasonographic features that support or reject the pathophysiology of the disease. Some particular conditions that lead to TTTS are mentioned in order to understand the disease better.

Summary of the Pathophysiology of Twin–Twin Transfusion Syndrome

TTTS presumably results from an unbalanced exchange of blood between two or more fetuses via placental vascular anastomoses. While this fundamental hypothesis has not been proven, circumstantial evidence suggests that this indeed may be the main operating pathophysiological mechanism.

The etiology of the unbalanced blood exchange can be traced back to either an abnormal design of the placental vascular anastomoses (obligatory etiology), or, less often, to primary hemodynamic differences between the fetuses. Hypovolemia in the donor twin elicits the RAS and increased ADH, causing local vasoconstriction, oliguria, oligohydramnios, and renal tubular dysgenesis. Hypervolemia in the recipient twin results in increased ANF secretion, polyuria, polyhydramnios, and hypertension.

Cause versus effect

The endocrine findings in TTTS are commonly viewed as the effect of the uneven blood exchange. Increased renin in the donor and increased ANF in the recipient, with their hemodynamic and renal consequences, follow the uneven exchange of blood. This view would be in accordance with the obligatory etiology as described above.

Alternatively, increased renin, increased ADH, and a tendency to raise the blood pressure in the donor could result from placental insufficiency. The increased blood pressure in the donor would in turn force more blood through placental vascular anastomoses into the recipient twin, setting off the vicious cycle.

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