Fetal Surgical Interventions

Eftichia Kontopoulos

Ruben Quintero

Ramen H. Chmait

Andrew H. Chon

Denise Araujo Lapa

Introduction

In 1994, Quintero and colleagues introduced the concept of operative fetoscopy.¹ The fundamental principles of this approach involve the percutaneous use of diagnostic or operating instruments under combined sonographic and endoscopic imaging. The goal of operative fetoscopy was to address all possible surgically correctable birth defects/conditions, without compromising maternal health or the course of the pregnancy. Since then, virtually all fetal and placental conditions have become amenable to antenatal treatment using this approach. The purpose of this chapter is to review the current status and future direction of operative fetoscopy for the treatment of the most salient fetal and placental disorders.

Treatment of TTTS

TTTS results from an uneven exchange of blood between the fetuses due to greater number or larger sized anastomoses from the donor to the recipient, which result in a larger volume of blood flow from donor to recipient. The placental vascular anastomoses present in TTTS include arteriovenous (AV), arterioarterial (AA), and venovenous (VV) anastomoses.² AV anastomoses have unidirectional flow from the donor to recipient (AVDR) or from the recipient to donor (AVRD). AA and VV anastomoses may have uni- or bidirectional flow. The uneven blood exchange between the fetuses produces hypovolemia, oliguria, and oligohydramnios in the donor twin and volume overload, polyuria, and polyhydramnios in the recipient twin.³^,⁴^,⁵^,⁶^,⁷ The diagnosis of TTTS requires fulfillment of the following ultrasound-based criteria: (1) monochorionicity; (2) single maximal vertical pocket (MVP) of amniotic fluid ≤2.0 cm on one side of the dividing membrane, and an MVP of ≥8.0 cm on the other side.⁵ The severity of the syndrome is classified according to the Quintero Staging System (Table 24.2),⁵ which has allowed researchers to compare outcome data obtained from various therapeutic modalities as well as predict perinatal survival after treatment.⁸ A detailed discussion of TTTS diagnosis and staging appears in Chapter 5.

Unless delivery of the fetuses can be considered, TTTS needs to be treated as soon as logistically feasible, mainly since the progression of the condition is unpredictable. Treatment of TTTS has included expectant medical management,⁹ sectio parva,¹⁰ serial amniocenteses,¹¹^,¹²^,¹³ and laser photocoagulation of the placental vascular anastomoses.¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹ However, the perinatal mortality rate of expectantly managed TTTS is as high as 95%,¹¹ and selective reduction via umbilical cord occlusion (UCO) (sectio parva) of one of the fetuses is an extreme measure that should only be entertained in extraordinary circumstances. Therefore, serial amniocentesis and laser therapy are the two approaches more commonly used, with laser photocoagulation being the treatment modality of choice.

Serial Amniocentesis

Serial amniocentesis, also called serial amniodrainage or amnioreduction, consists of removing the excessive amount of amniotic fluid from the recipient twin’s sac as often as necessary. Typically, an 18- to 20-gauge spinal needle is used.²⁰ The volume of amniotic fluid that should be withdrawn has not been standardized, although some authors suggest removing enough fluid to bring the MVP to approximately 6 cm.²¹ The purpose of reducing the amount of amniotic fluid volume in the recipient’s sac is to diminish the overall uterine distention and the risk of miscarriage or prematurity. An international registry of 223 patients with TTTS treated by serial amniocentesis showed perinatal survival of at least one twin of 70.8%.²² Although it is unclear whether all patients met criteria for TTTS based on today’s standards, the results were similar to amniocentesis-treated patients in two controlled nonrandomized trials that compared serial amniocentesis to laser therapy and reported a perinatal survival rate of 60.5%²³ and 66.7%.²⁴ Serial amniodrainage should be viewed as a contemporizing treatment measure, for it serves only to ameliorate the polyhydramnios, but does not treat the underlying etiology. Because the offending vascular communications remain patent, the physiologic stress of the syndrome to the fetuses is allowed to persist. Data regarding long-term neurodevelopmental outcome in cases of TTTS managed with amnioreduction have shown a rate of cerebral palsy between 5.8% and 22.5%, whereas the rate of developmental delay (non-cerebral palsy) ranged from 7.5% to 28.6%.²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰

Table 24.1 Comparison of Twin-Twin Transfusion Syndrome (TTTS), Selective Intrauterine Growth Restriction (sIUGR), and Twin Anemia-Polycythemia Sequence (TAPS)

Condition	Diagnostic Criteria	Amniotic Fluid Discordance	Growth Restriction	Growth Discordance >20%-25%	Role of Placental Vascular Anastomoses	Staging	Optimal Treatment
TTTS	MVP >8 cm in one twin, <2 cm in the other twin	Yes	May be present, but not part of the diagnosis	May be present, but not part of the definition	Causal	I-V, based on visualization of bladder, arterial and venous Dopplers, hydrops.	Laser photocoagulation of placental vascular anastomoses, regardless of stage.
SIUGR	EFW <10th percentile in one twin	May be present, but not >8 <2 cm.	Integral to the definition	May be present, but not essential to the definition	Causal, contributing, or only means of survival	Types I-III, based on diastolic flow in the umbilical artery	Laser ablation of placental vascular anastomoses, type II.
TAPS	MCA-PSV >1.5 MoM in one twin, <1.0 MoM in the other twin	May be present, but not >8 <2 cm.			Causal	I-V, based on MCA-PSV values, arterial and venous Dopplers, hydrops.	Laser ablation of placental vascular anastomoses
EFW, estimated fetal weight; MCA-PSV, peak systolic velocity of the middle cerebral artery; MoM, multiples of the median.

Table 24.2 Quintero Staging System of Twin-Twin Transfusion Syndrome (TTTS)

Stage	Bladder Visible	Critical Doppler Abnormalities in the Umbilical Artery, Umbilical Vein, Ductus Venosus	Hydrops	Demise of One or Both Twins
I	+	−	−	−
II	−	−	−	−
III	±^a	+^b	–	−
IV	±^a	+	+	−
V	N/A	N/A	N/A	+
^aStage III patients are subclassified into Donor, Recipient, or Donor-Recipient, depending on which twin has the critically abnormal Doppler findings.^bStage III-IV cases with a nonvisible bladder in the donor are classic. Stage III-IV cases with a visible bladder in the donor are considered atypical.

Laser Therapy

Unlike serial amniocentesis, laser therapy addresses the primary pathogenic cause of TTTS by ablating all vascular communications.¹⁸ This surgery is performed using fetal endoscopes, which are used to directly visualize the vessels on the placental surface. Once mapping of the vascular communications has been performed, the vessels are photocoagulated using a special type of laser energy that is delivered into the amniotic cavity by quartz fibers through the operating channel of the endoscope.

The surgical method of laser therapy has undergone several modifications to become what is successfully used today. The first technique lasered all vessels that crossed the intertwin dividing membranes.¹⁶^,¹⁷ Subsequently, Quintero et al developed the selective technique (selective laser photocoagulation of communicating vessels, or SLPCV), which selectively ablates only the vascular communications and does not require location of the dividing membrane.¹⁸ Ablation of all vascular anastomoses after SLPCV essentially transforms a monochorionic twin pregnancy into a “functional” dichorionic twin pregnancy, with no further exchange of blood between the fetuses.³¹ SLPCV is associated with at least one twin surviving in approximately 88% to 91% of cases³²^,³³ and a median gestational age at delivery of 33 6/7 weeks.³⁴

In two controlled nonrandomized trials that used similar diagnostic approaches and compared serial amniocentesis to laser therapy using the SLPCV technique, the at least one twin survival rate in the laser therapy arms was 79%²³ and 83.1%.²⁴ Combining the data of these studies, the survival rate in the amnioreduction group was 64.4% (78/121) versus 81.5% (137/168) in the laser group (P = .001). The short-term neurological morbidity in these studies ranged between 4.2% and 5.6%.

A randomized controlled trial conducted in Europe compared serial amniocentesis versus laser therapy.³⁵ The trial showed approximately a 4-week difference in pregnancy duration between the groups (29 vs 33 weeks, amniocentesis vs laser, respectively, P = .003),³⁵ and the amniocentesis group had significantly higher neurological complications (14% vs 6%, P = .02). This difference persisted at the 6-month follow-up evaluation.³⁵ Although, in retrospect, not all laser-treated patients underwent SLPCV (in fact, most underwent a nonselective technique), laser therapy was still superior to amniocentesis.

A third-generation laser technique has been reported,³³ which involves lasering the arteriovenous anastomoses in a specific sequence (sequential laser photocoagulation of communicating vessels, or SQLPCV), such that the AV anastomoses from the donor to the recipient are lasered first, followed by the remaining communications.³³ By performing the laser ablation in this sequential fashion, the donor twin is prevented from losing further blood into the recipient twin intraoperatively. This may be significant, even if the laser step of the procedure takes only 10 to 15 minutes. Furthermore, during such time, the donor twin receives an intraoperative transfusion from the recipient twin until all the AVRD anastomoses are ablated. In the original study describing the technique, SQLPCV resulted in increased dual survival rate compared to standard SLPCV (74% vs 57%, P = .005). The rate of at least one twin survivor was similar (91% vs 88%).³³ Although a sequential technique may not be required in all cases, it could be indicated in patients where the condition of the donor twin would be most compromised. The merits of performing SQLPCV versus SLPCV are being investigated through a randomized clinical trial conducted by the USFetus group³⁶ (clinicaltrials.gov identifier NCT02122328).

Table 24.3 Reported Incidence of Residual Patent Placental Vascular Anastomoses After Laser Surgery on Surgical Pathology Analysis of the Placentas

Author	Residual Patent Placental Vascular Anastomoses	P1	P2
Quintero (SLPCV),^38,39 2010	5/143 (3.5%)	–
Chmait (SLPCV),³⁷ 2010	5/100 (5%)	0.74
Lopriore (“Fetoscopic laser surgery”),⁴⁰ 2007	17/52 (33%)	<0.001
Slaghekke,^41-43 2014
“Standard”	26/77 (34%)	<0.001	>0.05
Solomon	14/74 (19%)	<0.001
SLPCV, selective laser photocoagulation of communicating vessels. Comparisons made relative to the lowest reported rate (P1) or between the “standard” and the Solomon techniques (P2).

Complications of Laser Therapy

The definitive treatment of TTTS requires that all placental vascular anastomoses be occluded. Incomplete (missed anastomoses) or inadequate (sublasered) laser ablation of the anastomoses leaves patent placental vascular anastomoses, which allow the fetuses to continue to exchange blood³⁷ (Table 24.3). Residual patent vascular anastomoses (RPVAS) may result in persistent TTTS (the condition continues) or reverse TTTS (the roles of the twins are reversed, such that the original donor becomes the new recipient, and the original recipient becomes the new donor). Persistent TTTS results from remaining AVDR anastomoses, whereas reverse TTTS results from remaining AVRDs. If both AVDRs and AVRDs remain patent, persistent or reverse TTTS may occur depending on the direction of the net exchange of blood between the fetuses.

Incomplete or inadequate laser therapy may also result in another condition, twin anemia-polycythemia sequence (TAPS), defined below and described in Chapter 5. If the demise of one twin occurs after surgery, incomplete or inadequate laser therapy may result in anemia or demise of the co-twin from postmortem fetofetal hemorrhage through the patent placental vascular anastomoses.

Failed laser surgery is defined as persistent or reverse TTTS or TAPS. Suspected anemia of a surviving twin after demise of the co-twin, by assessment of the peak systolic velocity of the middle cerebral artery (MCA-PSV), may also be due to RPAVs, although it may reflect the sequence of how the anastomoses were lasered. Dual fetal demise with postmortem demonstration of RPVASs is considered failed laser therapy. The rate of failed laser therapy varies significantly between 1% and 33% (Tables 24.3 and 24.4).⁴⁵

In view of the relatively high incidence of RPVAS seen by some groups, some authors proposed “connecting the dots” between photocoagulated areas on the surface of the placenta.⁴⁹ The premise behind this idea was that, by lasering spaces between laser-ablated placental vascular anastomoses, such “blind lasering” would capture “anastomoses” that would have been presumably missed (“not visible”).⁵⁰ The resulting surgical technique of lasering healthy interanastomotic areas of the placenta has been called the “the Solomon technique”⁴⁹ in reference to the biblical passage where, in order to resolve a dispute between two alleging mothers of the same child, King Solomon proposed to cut the baby in half (1 Kings 3:16-28, NIV). The analogy, therefore, is that by lasering the areas of the placenta between endoscopically identified and laser-ablated vascular anastomoses, the placenta would be “cut in half.”

To test whether the Solomon technique could indeed reduce the rate of RPVAS, an open-label randomized clinical trial was conducted in Europe (the Solomon trial) comparing the Solomon technique versus the “standard” technique (SLPCV).⁴¹^,⁴²^,⁴³ The study showed a decreased rate of persistent or reverse TTTS (2/137, 1% vs 9/135, 7%, Solomon vs “standard”, respectively, P = .03) and of TAPS (4/137, 2.9% vs 21/135, 15.5%, Solomon vs “standard”, respectively, P = <.001). Interestingly, the actual rate of RPVAS was no different between the two techniques (14/74, 19% vs 23/77, 29.8%, Solomon vs “standard,” respectively, P = .12). Although the primary outcome of the study was no different between the groups, the authors concluded that the Solomon technique was superior to the “standard” technique. Two additional observational studies comparing the Solomon technique with the selective technique also appeared to show favorable results with the former technique.⁴⁷^,⁴⁸ However, the superiority of the Solomon technique to the SLPCV technique has not been proven.

Table 24.3 shows the rate of residual patent placental vascular anastomoses reported by the different groups using either the Quintero selective (SLPCV) technique (ie, the “standard” approach) or the Solomon technique. As can be seen, the rate of RPVAS is lowest using the Quintero SLPCV. Table 24.4 shows that the Quintero SLPCV technique is also associated with a lower rate of persistent or reverse TTTS than that of the “standard” technique in the Solomon trial, and the “selective technique” of other authors and that the Solomon technique in all studies achieves the same rate of persistent or reverse TTTS than that reported with the Quintero SLPCV technique. Given that the Solomon technique is still associated with approximately 20% of RPVAS, the initial rationale for the technique, ie, to reduce the high rate of RPVAS, does not appear to hold. Furthermore, since the proponents of the Solomon technique have suggested that most missed anastomoses are located in the margins of the placenta,⁴⁶ lasering inexistent placental vascular anastomoses in otherwise healthy placental tissue between vascular anastomoses within the main body of the placenta is incongruent with the rationale (Table 24.5; Figure 24.1). Altogether, the Solomon technique would seem to represent a backward step in the ability to correctly identify all of the placental vascular anastomoses, by accepting the unproven theory of the presence of nonvisible placental vascular anastomoses in otherwise healthy-appearing placenta. Alternatively, we have shown that all of the placental vascular anastomoses can be clearly identified on the surface of the placenta. Stated differently, the use of the “Solomon technique” may simply represent an attempt to achieve similar results as those that can be obtained with the performance of the Quintero SLPCV technique, rather than a real advantage over the SLPCV technique, at the expense of lasering healthy placental tissue.

Table 24.4 Reported Incidence of Clinical Outcomes After Laser Therapy Reflecting Residual Patent Placental Vascular Anastomoses

Author	Reverse or Persistent TTTS	P
Chmait,³⁷ 2010	1/100 (1%)	–
Kontopoulos,⁴⁴ 2015	5/417 (1.5%)>	1.0
Robyr,⁴⁵ 2006	14/101 (13.8%)	.0006
Lopriore,⁴⁶ 2007	2/52 (3.8%)	.27
Slaghekke,^41-43 2014
“Standard”	9/135 (6.7%)	.046
Solomon	2/137 (1.5%)	1.0
Baschat,⁴⁷ 2013
“Selective”	6/71 (8.5%)	.02
Solomon	3/76 (3.9%)	.31
Ruano,⁴⁸ 2013
“Selective”	4/76 (5.3%)	.17
Solomon	0/26 (0%)	1
TTTS, twin-twin transfusion syndrome. Comparisons made relative to the lowest reported rate.

Table 24.5 Principles and Results of the Use of the Solomon Technique to Identify and Ablate all Placental Vascular Anastomoses in Twin-Twin Transfusion Syndrome

Purpose of the Surgery

Purported Location of the Residual Patent Placental Vascular Anastomoses

Actual Location of the Additional Laser Ablations

Rate of Residual Patent Placental Vascular Anastomoses^41-43

Rate of Residual Patent Placental Vascular Anastomoses (USFetus Group)^37-39

Decrease the rate of residual patent placental vascular anastomoses after laser therapy

Mostly on the margins of the placenta

Within the body of the placenta, between endoscopically identified vascular anastomoses

30% (“Standard”) vs 19% (Solomon)

P > .05

P < .05 relative to Solomon technique

Successful ablation of the placental vascular anastomoses assumes that the surgeon can conduct an adequate assessment of the placenta as well as occlude all of the offending anastomoses. Adequate placental assessment refers to the ability of the surgeon to survey the entire vascular equator. For example, in a subanalysis of the Solomon trial, the authors reported that they were able to adequately assess the placenta in only 65 out of 74 patients in the Solomon group (87%) and in only 69 out of 77 (89%) in the “standard” group,⁴¹^,⁴²^,⁴³ with inability to assess the placenta in 10%. If the placenta cannot be adequately assessed, this can result in missed anastomoses and thus an increased likelihood for persistent or reverse TTTS. In contrast, we have shown consistently the ability to assess the placenta adequately in over 99% of the patients.³⁴ Once all of the anastomoses have been identified, the next surgical competency benchmark refers to the ability of the surgeon to ablate the vascular anastomoses without including nonanastomotic vessels.³⁴^,⁴⁴^,⁵¹ For this, the surgeon must be able to adapt to the different clinical scenarios, including placental location, maternal habitus, and other challenging conditions.

Figure 24.1 A, Selective laser photocoagulation of communicating vessels (SLPCV). All of the anastomoses are photocoagulated, regardless of their location relative to the dividing membrane, while sparing nonanastomotic vessels. Rate of residual patent placental vascular anastomoses: 3.5% to 5%.³⁷^,⁴⁴ B, Solomon modification of the SLPCV technique. The fetal surface of the placenta between endoscopically identified anastomoses is also lasered to occlude “anastomoses” not visible by the endoscope. Rate of residual patent vascular anastomoses: 20%.⁴¹^,⁴²^,⁴³

Accuracy of Laser Therapy

Theoretically, one could combine the rate of adequate placental assessment and of selective laser surgery with the rate of either residual patent placental vascular anastomoses (when available) and the rate of persistent or reverse TTTS to determine how accurate the laser surgery is being performed at a given center or by a given surgeon. Accuracy of SLPCV could thus be defined as:

AccSLPCV = QSI × (1-RPPVA) × (1-PRTTTS)

where, AccSLPCV is the accuracy in performing SLPCV, QSI is the rate of Quintero selectively performed surgeries, RPPVA is the rate of residual patent placental vascular anastomoses (when available), and PRTTTS is the rate of persistent or reverse TTTS. Table 24.6 shows such a theoretical calculation and its use to compare outcomes of different reports.

Significant strides have been made both in establishing the scientific merit of using laser therapy to ablate the placental vascular anastomoses present in TTTS³⁵ as well as in the various steps, techniques, and other technical aspects that allow for such a therapy.

The development of the selective technique represented an important historical step in the surgical treatment of TTTS. A properly performed SLPCV technique is associated with the highest rate of clinical success and with the lowest rate of failed therapy either by surgical pathology or clinical criteria.⁵¹ Selective feticide via UCO should be the exception rather than the rule for severe cases of TTTS, and should not be performed to compensate for physician or surgical center limitations. Improvements in surgical competence, equipment, and other ancillary technology should continue to remain among the objectives of caregivers in this field.

Table 24.6 Accuracy of Laser Surgery for Twin-Twin Transfusion Syndrome (TTTS)

Author	Rate of Selectively Performed Surgeries	1-Rate of Residual Patent Placental Vascular Anastomoses	1-Rate of Persistent/Reverse TTTS	Accuracy of SLPCV
USFetus group^34,44	98.7%	0.95	0.99	92%
Solomon^41-43	87%	0.81	0.99	69.7%
Solomon^41-43 “standard”	89%	0.66	0.93	54%
SLPCV, selective laser photocoagulation of communicating vessels. 1- rate of adverse outcome, rate of success.

Neurodevelopmental Outcomes

While most studies on laser therapy for TTTS have focused on technical surgical aspects and perinatal survival rates, only a few have addressed the long-term developmental outcomes. A systematic review and meta-analysis, including eight international studies, showed that the prevalence of nonperinatal neurologic morbidity, an abnormal standardized test of neonatal development, or both was 11.1%, and the rates of cerebral palsy were 4% to 6%.⁵² A 2014 study in the United States on 100 children born after laser therapy for TTTS assessed with the Battelle Developmental Inventory, second edition (BDI-2) showed a total normal neurodevelopmental score of 103 (SD ±12). Individual child-level risk factors for lower BDI-2 included male sex (β = −0.37; P < .01), lower head circumference (β = 0.28; P < .01), and higher diastolic blood pressure (β = −0.29; P < .01). Lower maternal education (β = 0.60; P < .001), higher Quintero stage (β = −0.36; P < .01), and lower gestational age at birth (β = 0.30; P < .01) were associated with worse cognitive outcomes. Importantly, donor/recipient status, gestational age at surgery, fetal growth restriction, and co-twin fetal death were not risk factors. Only four children (4%) showed a neurodevelopmental impairment score of <70.⁵³

Twin Anemia-Polycythemia Sequence

Definition

Twin anemia-polycythemia sequence (TAPS) is a potential complication of monochorionic twins characterized by the presence of anemia in one twin and polycythemia in the other. Antenatally, TAPS is defined by the combination of an MCA-PSV >1.5 multiples of the median (MoM) in one twin and <1.0 in the other twin. Postnatally, the condition is defined by an intertwin hemoglobin difference of >8 g/dL, or an intertwin reticulocyte ratio >1.7.⁵⁴

TAPS was first mentioned as a complication of laser therapy for TTTS by Robyr et al in 2006⁴⁵ and subsequently as a spontaneous occurrence in a report of two cases by Lopriore et al in 2007.⁴⁰ Spontaneous TAPS (not iatrogenic) may also coexist with TTTS in approximately 2.4% of TTTS cases.⁵⁵ A 2015 article by Veujoz et al questioned the accuracy of the antenatal diagnostic criteria.⁵⁶ Indeed, Tollenaar et al showed that the standard MCA-PSV MoM >1.5/<1.0 combination had a sensitivity of only 46% against the postnatal gold standard.⁵⁷ Instead, a delta of 0.5 MoMs in the MCA-PSV of the two fetuses had a sensitivity of 83%. As a result, the authors suggest changing the antenatal criteria to a delta >0.5 MoMs in the MCA-PSV, rather than a fixed value of >1.5/<1.⁵⁷

The above controversy suggests that the definition of TAPS is still unsettled. Review of our laboratory data from a published cohort would have shown an incidence of 1% (2/193) versus 12.9% (25/193) cases of spontaneous TAPS + TTTS using the MCA-PSV >1.5/<1 MoM versus the delta 0.5 MoM definitions, respectively.⁵⁸ MCA-PSV MoMs are not routinely performed in second-trimester ultrasounds of monochorionic twins in the United States.⁵⁹ Given that the condition can exist in the absence of other sonographic abnormalities (ie, in the absence of polyhydramnios/oligohydramnios, growth restriction, abnormal Doppler findings in the umbilical artery, umbilical vein or ductus venosus, or fetal bladder filling), it is clear that the management guidelines should be changed to include routine Doppler examination of the middle cerebral in the second trimester in monochorionic twins to avoid missing the diagnosis of TAPS in these patients.⁶⁰

Pathophysiology and Staging

The pathogenesis of TAPS is presumed to be the result of a chronic slow net transfusion from the donor twin to the recipient twin, enough to cause large hemoglobin differences, but not enough to result in hemodynamic changes classic of TTTS, ie, without the polyhydramnios/oligohydramnios sequence. Spontaneous TAPS is typically associated with the presence of very small AV placental vascular anastomoses,⁶¹ although larger anastomoses and AA anastomoses have also been described.⁵⁵^,⁶²^,⁶³^,⁶⁴ Because TAPS has also been reported in the absence of placental vascular anastomoses,⁶⁵ these hallmarks may play a permissive but not an absolute role in the etiopathophysiology of TAPS.

A staging system for TAPS was proposed by Slaghekke et al in 2010⁵⁴ and then modified by Fishel-Bartal et al in 2016 using a delta >0.5 MoMs for the MCA-PSV.⁶⁶ Table 24.7 shows the original and the modified systems.

Treatment of TAPS and Outcomes

The treatment options that have been proposed for patients with TAPS include expectant management, intrauterine transfusion (IUT) of the anemic twin, and partial exchange transfusion (PET) of the polycythemic twin, laser therapy, or cord occlusion of one of the fetuses. A recent review of the literature suggested that laser therapy was associated with a 15% mortality rate and 18% risk of adverse perinatal outcomes; expectant management was associated with a 10% mortality rate and 75% risk of adverse perinatal outcomes; and IUT/PET was associated with a 16% mortality rate and a 43% risk of adverse pregnancy outcomes.⁶⁷

Intrauterine transfusions and partial exchange transfusions may result in postnatal morbidity to either twin. The recipient twin may develop polycythemia hyperviscosity syndrome, including skin necrosis and limb ischemia and thrombocytopenia.⁴⁵^,⁶⁸^,⁶⁹^,⁷⁰ Neurological damage of the donor or the recipient twin has also been reported either spontaneously or with IUT and PET.⁷¹ Long-term neurodevelopmental morbidity after laser therapy has also been reported.⁴¹^,⁴²^,⁴³^,⁶⁵ The rates of mild and moderate neurodevelopmental impairment (9% and 17%, respectively) are similar to those reported for the treatment of TTTS using the Solomon technique.⁷²

Additional information on TAPS can be found in Chapter 5.

Selective Intrauterine Growth Restriction

Incidence

Selective intrauterine growth restriction (sIUGR) occurs in approximately 12.5% to 25% of all monochorionic pregnancies.⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷ The actual incidence is difficult to ascertain because the distinction between TTTS and pure sIUGR may not have been made in earlier series. For example, pure sIUGR can be present in up to 15% of monochorionic twins initially thought to have had TTTS,⁷³ and IUGR coexists with TTTS in approximately 50% of patients.³³^,⁷⁸ Other problems in establishing the actual incidence of the condition stem from lack of consensus in its definition.

Table 24.7 Proposed Antenatal Classification System for Twin Anemia-Polycythemia Sequence (TAPS)⁵⁷

Antenatal Stage	Previous Criteria⁵⁴	Proposed Criteria⁵⁷
Stage 1	MCA-PSV donor >1.5 MoM, recipient <1.0 MoM; without signs of fetal compromise	Delta MCA-PSV >0.5 MoM; without signs of fetal compromise
Stage 2	MCA-PSV donor >1.7 MoM, recipient <0.8 MoM; without signs of fetal compromise	Delta MCA-PSV >0.7 MoM; without signs of fetal compromise
Stage 3	As stage 1 or 2; with cardiac compromise of donor^a	As stage 1 or 2; with cardiac compromise of donor^a
Stage 4	Hydrops of donor	Hydrops of donor
Stage 5	Intrauterine demise of one or both fetuses preceded by TAPS	Intrauterine demise of one or both fetuses preceded by TAPS
MCA-PSV, middle cerebral artery peak systolic velocity; MoM, multiples of the median.
^aDefined as critically abnormal flow: Doppler shows absent or reversed end-diastolic flow in umbilical artery, pulsatile flow in umbilical vein and/or increased pulsatility index or reversed flow in ductus venosus.
Reprinted from Tollenaar LSA, Lopriore E, Middeldorp JM, et al. Improved prediction of twin anemia-polycythemia sequence by delta middle cerebral artery peak systolic velocity: new antenatal classification system. Ultrasound Obstet Gynecol. 2019;53(6):788-793.

Definition of sIUGR

Quintero et al defined sIUGR as an estimated fetal weight (EFW) <10th percentile for one twin (SIUGR twin), while the other twin is appropriate for gestational age (AGA) (EFW between 10th-90th percentile).⁷³ The rationale for this definition stems from the fact that in singletons, IUGR is defined as a sonographic EFW <10th percentile.⁷⁹ Recent data suggest that singleton charts may be used up to 28 weeks for monochorionic twins and up to 32 weeks for dichorionic twins, after which the fetal weights are significantly lower than in singletons.⁸⁰^,⁸¹^,⁸²

EFW discordance between the twin pair has also been used as a proxy for the diagnosis of sIUGR. However, only 50% of sIUGR patients have an intertwin EFW discordance of >20%⁸³ Furthermore, both fetuses can be AGA and yet have an EFW >20% to 25%.⁸⁴

Some authors have suggested using a combination of discordance >25% and EFW <10th percentile,⁸⁵ EFW <5th percentile,⁸⁶ or three out of four of the following criteria: EFW of one twin <10th percentile, abdominal circumference (AC) of one twin <10th percentile, EFW discordance of 25% or more, umbilical artery pulsatility index (UA PI) of the smaller twin above the 95th percentile. By definition, the sensitivity of the diagnosis is decreased with each additional criterion besides EFW <10th percentile. Thus, the diagnosis of sIUGR should be based solely on an EFW <10th percentile in one of two monochorionic twins before 28 weeks of gestation.⁸⁷

Classification of sIUGR

A classification of sIUGR into three types—type I, II, and III—based on the diastolic waveform pattern of the umbilical artery Doppler in the smaller twin has been proposed.⁸⁷ Type I, with diastolic flow; type II, with absent end-diastolic flow (AEDV); and type III, with intermittent absent or reversed end-diastolic velocity flow (AREDF). Although the classification system implies that the lower the type, the better the prognosis, subsequent studies have failed to find worse outcomes in type III patients versus type I or II patients.⁸⁸ In fact, type I and type III patients appear to have a similarly better prognosis than type II patients. Thus, the current classification of sIUGR is misleading and should not be used to recommend cord occlusion in type III patients.

Etiology

sIUGR is thought to be the result of a failure of the individual placental territory (IPT)⁸⁹ of one twin to satisfy the nutritional aspects of that fetus. Although sIUGR may occur from an actual suboptimal IPT, it may also result from the presence of placental vascular anastomoses, despite an adequate IPT for the SIUGR twin.⁹⁰^,⁹¹

Role of Placental Territory and Placental Vascular Anastomoses

Traditionally, growth restriction of the of one twin has been thought to be the result of placental insufficiency.¹¹^,¹⁷ Unequal placental sharing may explain the pathogenesis of severe discordance and sIUGR in twin gestations as well as postoperative intrauterine fetal demise (IUFD) of a single fetus after laser surgery.¹⁷^,²³^,²⁴ To better define unequal placental sharing, Quintero introduced the concept of percent individual placental territory (%IPT)⁸⁹ defined as the individual placental mass (IPM) of one fetus divided by the total placental mass × 100. Indeed, the %IPT was significantly smaller in the donor twin relative to the recipient twin in a series of TTTS patients.⁸⁹ Interestingly, however, the %IPT was not different between donor twins and control small twins, yet the birth weights of donor twins were significantly smaller than control small twins, controlled for gestational age.⁸⁹ This suggests that growth restriction is not only the result of having a smaller %IPT. Instead, placental vascular anastomoses, particularly of the AA type, may be implicated in the unexplained excess growth restriction of certain monochorionic twins.⁸⁹

Role of AA Anastomoses

AA anastomoses consist of an arterial vessel that connects the circulations of the two fetuses uninterruptedly. As such, both twins pump blood in opposite directions through the same vessel. Such vessels typically have branches that perfuse cotyledons of one or the other twin. Depending on the pressure gradient between the two fetuses and the location of the arterial branches, AA anastomoses may behave as bidirectional or unidirectional (with AV) placental vascular communications.⁹²

AA anastomoses are present in approximately 50% of patients with sIUGR.⁹² Indirect demonstration of the possible etiological role of AA anastomoses in sIUGR is suggested by improvement of the umbilical artery Doppler indices⁷³ and catch-up growth⁹³ after laser therapy.

Management

Current counseling of patients with sIUGR involves consideration of the following management options: expectant management, UCO, termination of pregnancy, or laser therapy.

Expectant Management

Expectant management of patients with sIUGR may be associated with an increased risk of adverse perinatal outcomes, including prematurity and its attendant complications.⁸⁸ Increased risk for spontaneous demise of the sIUGR twin may result in the concomitant demise of the AGA twin in up to 40% of cases or in neurologic damage of the AGA twin in up to 30% of cases.⁹⁴^,⁹⁵^,⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶ The adverse effects on the AGA twin resulting from the spontaneous demise of the sIUGR twin stem from postmortem fetofetal hemorrhage from the AGA twin to the demised sIUGR twin through patent placental vascular communications.¹⁰⁰^,¹⁰⁷

The risk of adverse outcomes may be higher depending on the umbilical artery Doppler waveform of the sIUGR fetus, such that fetuses with persistent AEDV (sIUGR type II) are thought to be at a higher risk than sIUGR fetuses with umbilical artery forward diastolic flow (sIUGR type I).⁸⁸^,¹⁰⁸ Fetuses with intermittent AEDV (sIUGR type III) are believed to have an unpredictable prognosis.⁸⁷ To avoid the potential complications associated with expectant management, patients with sIUGR are often asked to consider either termination of pregnancy or cord occlusion of the sIUGR twin.¹⁰⁹ Expectant management is also associated with 100% risk of iatrogenic premature delivery, which is performed to avoid the adverse effects of the potential demise of the sIUGR twin, except in those cases where demise of the sIUGR has already occurred spontaneously, after cord occlusion, or after laser therapy. Patients are typically followed every 1 to 2 weeks with serial ultrasound examinations to monitor for sonographic evidence of deterioration (eg, change from type I to type II, or abnormal venous Dopplers). Some patients are hospitalized for closer surveillance and corticosteroids administration for fetal lung maturity enhancement. Finally, TTTS may develop in a subset of sIUGR patients, in which case laser therapy can be offered before 26 weeks of gestation. In the unfortunate event of single twin demise prior to 34 weeks, it is recommended that delivery of the surviving co-twin be postponed until at least 34 weeks⁹⁴ unless other obstetric indications require immediate delivery.

Umbilical Cord Occlusion

Selective feticide of the sIUGR twin in monochorionic pregnancies is aimed at sparing the surviving AGA twin from the risks of the spontaneous demise of the sIUGR twin. Several methods have been described, including intravascular injection of fibrin glue,¹¹⁰ metal coils,¹¹¹^,¹¹²^,¹¹³^,¹¹⁴ or alcohol-embedded suture material¹¹⁵; induction of cardiac tamponade¹¹⁶; and utilization of clips.¹¹⁷ The main limitation of any of these techniques is the inability of the operator to isolate the co-twin’s circulation. As a result, fetofetal hemorrhage and thromboembolic events can cause the concomitant death of the healthy twin. Other approaches include fetoscopic and ultrasound-guided UCO,¹ which results in instantaneous, complete interruption of the blood flow; bipolar coagulation; and radiofrequency ablation.¹¹⁸ Survival of the AGA twin ranges from 87.5% to 100%.⁷³^,¹¹⁸^,¹¹⁹ Although UCO of the sIUGR twin may be an effective method to treat the condition, it should only be offered in extreme cases where spontaneous demise of the sIUGR twin is highly anticipated.

Laser Therapy

The rationale for laser therapy to treat sIUGR stems from the fact that placental vascular anastomoses mediate the adverse effects on the AGA twin which occur as the result of the spontaneous demise of the sIUGR twin. Thus, occlusion of the anastomoses interrupts the blood exchange between fetuses, rendering them functionally as dichorionic twins. Laser therapy for sIUGR was first described by Quintero et al in a small study, which compared outcomes of 11 sIUGR pregnancies that underwent SLPCV versus 17 sIUGR pregnancies that were expectantly managed.⁷³ Although there was no difference in fetal survival, neurological morbidity was 0% in the laser group versus 13.6% in the expectantly managed group, and laser therapy associated with improvement in the Doppler studies in 3 of 11 sIUGR twins.

Vanderbilt et al completed a study in 2014, which examined the postnatal neurodevelopment of the children of 20 patients who were antenatally diagnosed with type II sIUGR.⁵³ Women were randomly assigned to receive expectant management (EM) or laser therapy (LT). Neurodevelopmental impairment (NDI) was also assessed, in accordance with previous TTTS literature.⁵³ Composite scores for the AGA and IUGR twins were compared by treatment arm. The mean standard deviation (SD) of the gestational age (GA) at diagnosis was no different between the EM and LT groups (21.5 [2.0] vs 21.1 [2.8] weeks, P = .7414, respectively). However, GA at delivery was significantly lower in the EM versus the LT group (28.3 [1.8] vs 33.4 [3.8] weeks, P = .0039). Neurodevelopment of the offspring was conducted using the BDI-2, and neurodevelopmental impairment was assessed per previous TTTS literature. There were no differences in overall BDI-2 scores between the EM and LT groups and no differences in the individual domains for the AGA and sIUGR infants. However, there was a tendency for motor development of the IUGR twin to be significantly better in the LT group, compared to the EM group (P = .062). Given the significantly higher GA at delivery for the LT group, in a larger cohort, it is possible that neurodevelopmental differences would become apparent, in favor of laser treatment.

Twin Reverse Arterial Perfusion Sequence

Twin reverse arterial perfusion sequence (TRAP) occurs in the presence of an artery-to-artery and vein-to-vein anastomosis between the twins,¹²⁰^,¹²¹ which causes one fetus (pump twin) to perfuse the other fetus (perfused twin or “acardiac fetus”) in a retrograde fashion (see Chapter 5).¹²² The perfused twin’s intake of deoxygenated blood results in severe maldevelopment and incompatibility with life outside of the womb. Risk factors for poor perinatal outcomes include polyhydramnios, critically abnormal Doppler, or hydrops on the pump twin side, and large size of the perfused twin (greater than 50% of the pump twin).¹²³ If one or more of these factors are present between 16 and 26 weeks’ gestation, the patient should be offered the option of UCO of the perfused twin.

Treatment

The first successful UCO for TRAP sequence was performed by Quintero et al in 1994¹ and was subsequently refined.¹²³ Criteria for UCO included the presence of at least one of the following: (1) abdominal circumference of the perfused twin equal to or greater than the pump twin, (2) polyhydramnios (MVP > 8 cm), (3) abnormal Doppler studies in the pump twin, (4) hydrops of the pump twin, or (5) monoamniotic twins. The initial procedure used a two-trocar technique, which evolved to a single-trocar technique without purposeful disruption of the dividing membranes. Perinatal outcomes in patients who underwent UCO were significantly better than those who were expectantly managed if the dividing membranes were not purposely disrupted, with the best perinatal outcomes obtained if operative fetoscopic UCO was performed within the sac of the perfused twin.¹²³

Fetoscopic UCO can be performed using a variety of surgical techniques, each of which is particularly suited to a given clinical presentation. The most important preoperative consideration is surgical access.¹²³ Entering the sac of the perfused twin offers all of the possible occlusion alternatives. In addition, if rupture of the sac of the perfused twin occurs, it may not necessarily affect the pump twin. Disruption of the dividing membrane should be avoided at all times.¹²³

The choice of surgical technique depends on the specific characteristics of the cord and of the vascular anastomoses. Umbilical cord laser photocoagulation or laser of the vascular communications are possible options, if the cord is not amenable to ligation. Bipolar electrocautery is also an alternative, although this technique can be limited by the size of the umbilical cord and may result in bleeding from the cord itself.¹²⁴ One of the limitations of intrafetal radiofrequency ablation is that the extent of the thermal damage is not entirely under the control of the operator, and intraoperative exsanguination of the pump twin may occur, which may result in intrafetal hemorrhage and death.¹²⁵^,¹²⁶

Discordant (Obligate Lethal) Anomalous Twins

Patients with monochorionic twins discordant for the presence of an obligate lethal condition other than TRAP, such as anencephaly or other severe congenital anomaly in which the affected twin has a significant risk of in utero demise and, thus, poses a risk to the co-twin, can be offered the option of UCO. The presence of discordance itself is not an indication for UCO. Unlike dichorionic twins, injection of potassium chloride cannot be performed in monochorionic twins because of possible transmission of the lethal substance to the co-twin through the vascular anastomoses. Thus, UCO is utilized in a similar fashion as described for TRAP sequence. UCO in these patients may be technically easier than in TRAP cases, as access to the cavity of the anomalous twin may not necessarily be hindered by oligohydramnios. If the anomalous twin does not represent a threat to the healthy co-twin (either hemodynamically or from risk of spontaneous death or polyhydramnios), expectant management rather than UCO is indicated.

DEVELOPMENTAL STRUCTURAL ABNORMALITIES

Fetal Lung Masses

Thoracic Space-Occupying Lesions

Pulmonary hypoplasia and subsequent neonatal death may result from various space-occupying lesions, including congenital diaphragmatic hernia (CDH), cystic adenomatoid malformation (CCAM) (also known as congenital pulmonary airway malformation [CPAM]), lobar or extralobar bronchopulmonary sequestration (BPS), pulmonary emphysema, bronchial atresia, and hydrothorax, among others (Table 24.8).¹²⁷^,¹²⁸^,¹²⁹ The mechanism by which space-occupying lesions result in pulmonary hypoplasia is thought to be due to arrest of normal embryological lung development.

Fetal therapy may be considered in select cases to counter the effect of the lesion and avoid the development of pulmonary hypoplasia.¹²⁷^,¹³⁰^,¹³¹^,¹³² The fundamental steps required to offer fetal therapy include an as accurate as possible prenatal differential diagnosis, knowledge of the natural history of each condition, development of antenatal criteria for intervention, and appropriate form of treatment. Prenatal differential diagnosis can be undertaken using ultrasound, color and pulsed Doppler, as well as fetal magnetic resonance imaging (MRI). In particular, the differential diagnosis between CCAM/CPAM, pulmonary sequestration, and pulmonary emphysema may be difficult, especially if an obvious feeding vessel stemming from the aorta cannot be distinctly identified using ultrasound.¹³³ The differential diagnosis is also important because as many as 60% of CCAM/CPAM lesions may regress spontaneously¹²⁷; therefore, the appropriate fetal therapeutic approach might be to continue to manage the pregnancy expectantly.³³^,¹³⁴^,¹³⁵

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