Objective
The purpose of this study was to evaluate the phenomenon of vascular ischemic limb necrosis in twin-twin transfusion syndrome (TTTS).
Study Design
This was a multicenter retrospective review of ischemic limb necrosis in patients with TTTS.
Results
Twenty cases of fetal ischemic limb necrosis in association with TTTS were identified from 10 fetal medicine centers. The recipient was affected in 19 cases, and the lower limb was affected in 17 cases. The extent of the damage correlated with TTTS severity. Eighty percent of limb defects (16/20) clearly were unrelated to laser treatment (3 cases untreated, 7 cases after amnioreduction, 6 cases present at time of laser). The recipient was relatively polycythemic in 5 of 7 cases in which neonatal or fetal hemoglobin/hematocrit levels were available.
Conclusion
Ischemic limb necrosis is a rare complication of TTTS. The lesion is unrelated to therapy and may be the result of polycythemia, hypertension, and vasoconstriction.
Twin-twin transfusion syndrome (TTTS) occurs in 10-15% of monochorionic twin pregnancies. Without treatment, the fetal mortality rate in severe TTTS is as high as 90%, and morbidity includes hydrops and cerebral, cardiovascular, and renal complications. Selective laser ablation of the placental anastomoses increases survival to 55-93%. Antenatal ischemic limb injury is a rare complication of TTTS. The incidence of vascular limb occlusion is reported at 0.52% (4/755) for monochorionic twins in general and 0.51% (2/391) for those cases that are complicated by TTTS; these data are from a large series of monochorionic twins that were observed at 2 fetal therapy centers in the Netherlands and Belgium. Therefore, vascular limb defects appear to be at least 10-fold more frequent in monochorionic twins than in the general population, where a prevalence of 0.02% has been reported. Previously, 18 limb defects in TTTS have been published as reports of 1 or 2 cases. Various pathologic mechanisms have been suggested that have included polycythemia-hyperviscosity syndrome, elevated angiotensin level, release of thrombi after co-twin death, umbilical arterial-steal syndrome, vascular injury, and laser-induced thrombi. This phenomenon has never been studied in a large patient population, and the exact pathophysiologic mechanism remains to be elucidated.
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We conducted a retrospective study of cases of vascular limb injuries in TTTS that were reported from 10 fetal medicine centers. Our aim was to evaluate the characteristics of this rare complication in a larger patient population and to review the possible pathophysiologic mechanism. We compared our series with previous case reports of this phenomenon.
Methods
This was a retrospective, multicenter study conducted in 10 perinatal centers in Germany, the United States, Jordan, Argentina, Israel, and Canada. Five of these centers were regional laser centers for the treatment of TTTS. Data that were evaluated included gestational age at diagnosis, TTTS stage, type of treatment (laser and/or amniocentesis), affected twin (donor or recipient), affected limb (upper or lower, right or left), extent of defect (total necrosis/amputation vs only skin defect, above or below knee, above or below elbow), timing of the diagnosis, fetal/neonatal hemoglobin or hematocrit level, and perinatal outcome. Cases where the limb defect might have been associated with amniotic bands or direct thermal injury were excluded. Neonatal polycythemia was defined as Hematocrit or Hemoglobin level of >95th percentile for gestational age; anemia was defined as Hemoglobin level of <5th percentile for gestational age. Extensive necrosis was defined as a defect above the knee that affected tissues deeper than the skin. A literature search in PubMed was performed to identify previously reported cases to compare with our series; authors were contacted if additional data were required. The study was approved by the research ethics board (REB no.11-0080-C).
Results
Current series
Twenty cases of limb reduction were identified either antenatally (on ultrasound scanning or fetoscopy) or at birth. The mean gestational age at the time of diagnosis of TTTS was 21.8 ± 2.41 weeks (16-26 weeks). Neither stage nor gestational age at referral differed between laser and nonlaser centers. No mother had a history of thrombophilia or any thromboembolic event. In 95% of cases (19/20), the limb defect occurred in the recipient twin; in 85% of cases the defect in the lower limb (17/20), of which 71% of the defects (13/17) were on the right ( Tables 1 and 2 ; Figures 1-5 ; Video Clip ).
| Patient | Twin-twin transfusion syndrome diagnosis | Affected twin | Affected limb | Location of injury | Fetal therapy | Method and timing of diagnosis (wk) | Postnatal course and pediatric surgical management | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Gestational age, wk | Stage | Side | Extent a | Description | ||||||
| 1 | 21.8 | IV | R | LL | Left | 1 | Above knee | L (+3xA) b | Fetoscopy (22) | Amputation |
| 2 | 21.6 | IIIR | R | LL | Right | 0 | Toes | L | Fetoscopy (21.6) | N/A; IUD |
| 3 | 20.6 | II | R | LL | Right | 0 | Syndactyly, absent endophalanges, club foot, hypertrophic lower limb | L | Postnatal (27.1) | N/A; IUD |
| 4 | 20.6 | II | R | UL | Left | N/A | Hand, digits 2,3, and 4 | L | Fetoscopy (20.7) | Hand missing at birth |
| 5 | 24.3 | II | R | LL | Right | 0 | Toes nearly amputated, skin necrosis from knee down | L | Postnatal (34.7) | No amputation |
| 6 | 20 | V | R | UL | Both | N/A | Not all bones present | None | US (20) | N/A; IUD |
| 7 | 20.3 | II | D | UL | Left | N/A | Fingers/skin of hand | A (1 time) | Postnatal (28.2) | Fingers amputated at 7 wks |
| 8 | 19.8 | II | R | LL | Left | 0 | Toes 1 and 2 absent, club foot | L | Fetoscopy (19.8) | No amputation, developmental delay |
| 9 | 25.9 | II | R | LL | Left | 1 | Including upper part of limb | A (1 time) | Postnatal (26.) | Amputation |
| 10 | 19.5 | 1 | R | LL | Right | 0 | Toes, gastrocnemius much smaller | A (8 times) | Postnatal (28.2) | Atrophic calf, tendon release at 15 mo |
| 11 | 20.1 | IIIR + IIID | R | LL | Right | 0 | Below knee | A (7 times) | Postnatal (29.4) | Below knee amputation at 6 d |
| 12 | 23.5 | IIIR | R | LL | Right | 1 | Above knee | A (1 time) | Postnatal (25.8) | Neonatal death |
| 13 | 20.4 | IV | R | LL | Right | 1 | Above knee | L (+2 A) b | US after laser therapy (28) | Midthigh amputation |
| 14 | 22.4 | IV | R | LL | Right | 1 | Above knee | L | Fetoscopy (22.6) | N/A; IUD |
| 15 | 21.4 | IIIR | R | LL | Left | 0 | Below knee | L | Postnatal (34.1) | Below knee amputation |
| 16 | 16 | II | R | LL | Right | 0 | Below knee | A (2-3 times) | Postnatal (30.3) | Right through knee amputation day 3 |
| 17 | 22.4 | IIIR + IIID | R | LL | Right | 1 | Above knee | A (4 times) | Postnatal (28.5) | N/A; IUD |
| 18 | 26 | IV | R | LL | Right | 1 | Above knee | None | Postnatal (28) | Distal femur amputation |
| 19 | 25 | I | R | LL | Left | 1 | Above knee | None | Postnatal (32.6) | Amputation above knee |
| 20 | 23.9 | IIIR + IIID | R | LL | Right | 1 | From hip down | A + L (24 wk) | Fetoscopy | N/A; termination of pregnancy |
a 1 = above knee; 0 = below knee;
b Amnioreduction was always performed at fetoscopy; only additional amnioreductions are mentioned.
| Variable | Our series (n = 20) | Published case reports (n = 16) |
|---|---|---|
| Diagnosis | ||
| Mean gestational age, wk | 21.8 (95% CI, 16–26) | 21.5 (95% CI, 17–28) |
| Stage, n | ||
| I | 2 | 2 |
| II | 7 | 2 |
| III | 6 (3 D + R; 3 R) | 7 (2 D + R; 3 R; 1 D; 1 N/A) |
| IV | 4 | 1 |
| V | 1 | 2 |
| Oligohydramnios/polyhydramnios sequence | 1 | |
| Recipient/donor, n | 19/1 | 15/1 |
| Affected limb, n | ||
| Lower | 17 (Right, 13; left, 4) | 13 (Right, 6; left, 7) |
| Upper | 3 (Left, 2; bilateral, 1) | 3 (Right, 2; left, 1) |
| Cases with extensive necrosis above the knee, n | 9 (Stage IV, 4; stage IIID + IIIR, 2; stage IIIR, 1; stage II, 1; stage I, 1) | 4 (Stage V, 1; stage IV, 1; stage IIID + IIIR, 1; stage III not further specified, 1) |
| Cases with limited necrosis below the knee/elbow or skin only, n | ||
| Lower limb | 8 (Stage IIIR, 2; stage IIID + IIIR, 1; stage II, 4; 1 stage I, 1) | 9 (Stage V, 1; stage IIID + IIIR, 1; stage IIIR, 2; stage IIID, stage III not further specified: 1; 1; stage II, 1; stage I, 1; oligohydramnios/polyhydramnios sequence, 1) |
| Upper limb | 3 (Stage II, 2; stage V, 1) | 3 (Stage IIIR, 1; stage II, 1; stage I, 1) |
| Fetal therapy, n | ||
| Laser | 10 a | 5 |
| Amnioreduction only | 7 | 7 |
| Untreated | 3 | 4 |
| Time/mode of diagnosis, n | ||
| Postnatal | 12 (After laser therapy, 3; after amnioreduction only, 7; untreated, 2) | 9 (After laser therapy, 3; after amnioreduction, 6) |
| Antenatal | 8 (During fetoscopy, 6; ultrasound scanning in an untreated case, 1; ultrasound scanning at 9 wk after laser therapy, 1) | 3 (Ultrasound scanning after laser therapy, 2; ultrasound scanning after amnioreduction, 1) |
| Mean gestational age at delivery, wk | 29.1 (95% CI, 20–35.8) | 30.2 (95% CI, 26–38) |
| Twin survival, n | ||
| Both alive | 9 (45%) | 9 (56%) |
| One alive | 6 (30%) b | 5 (31%) c |
| No survivors | 5 (25%) | 2 (13%) d |
a In 6 laser-treated cases, the defect was already present at the time of laser;
b 3 donors died (intrauterine death, 1; neonatal deaths, 2); 3 recipients died (intrauterine deaths, 2; neonatal death, 1);
c 4 donors died (intrauterine deaths, 2; neonatal deaths:2); 1 recipient died (neonatal death);
The extent of the defect seemed to correlate with TTTS severity; most of the cases with severe lower limb defects occurred in stages III or IV TTTS (7/9; 78%), the incidence of stage III or IV TTTS was low in cases with less extensive defects (3/8; 37%). All 3 lesions in the upper limb were limited to the hand, 2 of which were unilateral (stage II) and 1 was bilateral (stage V). In the only case that involved a donor, the left upper limb was affected (stage II).
Amnioreduction alone or laser therapy plus amnioreduction were planned for all but one patient (case 19; stage I). In 2 cases, therapy could not be carried out because one (case 18) or both twins (case 6) died before the planned intervention.
Eight defects (40%) were diagnosed antenatally, 6 on fetoscopy before the initiation of laser therapy and 2 on ultrasound scanning (one was diagnosed 7 weeks after laser therapy [case 13]) and one in an untreated case (case 6). Twelve defects (60%) were detected postnatally; laser therapy been performed in only 3 cases; in those 3 cases, the defect was always more limited. Case 3 had laser therapy at 20.6 weeks’ gestation (stage II) with improvement of TTTS. The patient was delivered at 27.2 weeks’ gestation after intrauterine death of the donor; the recipient had absent endophalanges and hypertrophy of the right lower leg. Case 5 had laser therapy at 24.4 weeks’ gestation (stage II) with improvement of TTTS; limited necrosis of the recipient’s right lower limb (skin necrosis and amputated toes) was noted after delivery at 34.7 weeks’ gestation. The third case (case 15) was treated with laser therapy (stage IIIR) at 22.9 weeks’ gestation, with improvement of TTTS; limited necrosis of the recipient’s left lower limb was detected at cesarean section delivery at 34.3 weeks’ gestation.
In all but one untreated case and in all cases with amnioreduction alone, the limb defects were diagnosed postnatally.
Neonatal outcome was available for all 20 cases ( Tables 1 and 2 ). Survival was equal between donors and recipients. In pregnancies in which only 1 twin survived, 3 recipients and 3 donors died: 1 recipient (stage IV) died neonatally at 6 weeks’ of life of necrotizing enterocolitis and sepsis (case 1), and the other 2 recipient deaths were in-utero at 27 weeks’ gestation (one death [case 3] with intrauterine growth restriction); the other death (case 14) with hydrops at 4 weeks after laser therapy for stage IV TTTS. The 3 donors died either in the immediate neonatal period (2 stage II cases [cases 9 and 16]) or in-utero shortly after transfer to the laser center, but before treatment (1 stage IV; case 18).
In the 5 cases with no survivors, 2 cases were double fetal deaths. In one case, the recipient died at 22 weeks’ gestation (stage IIIR), and the donor died during premature delivery at 23.4 weeks’ gestation (case 2). In the other, both twins died in-utero at 20 weeks’ gestation (case 6). Of 2 other cases with no survivors, one case had a dual neonatal death at 25.8 weeks’ gestation (case 12; Figure 2 ); in the other case, the recipient died in-utero at 25.5 weeks’ gestation, and the donor died neonatally after delivery by cesarean section at 28.5 weeks’ gestation (case 17; Figure 3 ). The fifth patient with no survivors elected to terminate her pregnancy after viewing the fetoscopy video that showed an extensive lesion in the recipient’s right leg (case 20; Clip 1).
Neonatal outcome and limb management are reported in all patients ( Tables 1 and 2 ). Whereas all 5 surviving fetuses with extensive necrosis required an above-knee amputation within a few days of birth, 2 of the 6 survivors with less extensive lower limb lesions (cases 5 and 8) and 1 of the 2 survivors with upper limb lesions (case 4) were observed expectantly.
Fetal or neonatal hemoglobin or hematocrit values were available in 35% of cases ( Table 3 ). Relative polycythemia was present in 6 recipients and 1 donor.
| Case | Polycythemia in recipient a | Polycythemia (values after birth) | Donor | Difference of Hb/Hct values, % |
|---|---|---|---|---|
| Recipient | ||||
| 2 | 1 | Hb 170 g/L (fetal blood sampling) | ||
| 4 | 0 (Donor polycythemic) | Hb 164 g/L; Hct 54.3% | Hb 223 g/L; Hct 72.4% | 27 |
| 7 | 1 b | Hb 187g/L; Hct 56% | Hb 92 g/L; Hct 28% | 51 |
| 9 | 1 | Hb 206 g/L; Hct 60% | ||
| 10 | 0 | Hb 152 g/L; Hct 47.6% | ||
| 11 | 1 | Hb 180 g/L | Hb 57 g/L | 68 |
| 16 | 0 | Hb 151 g/L; Hct 43.3% | Hb 135 g/L; Hct 38.8% | 11 |
| 18 | (1) c | Erythrocytosis | Anemia | |
| 19 | 1 | Hb 227 g/L; Hct 68.4% | Hb 140 g/L; Hct 41.95% | 38 |
| 21 | 1 | Hb 150 g/L; Hct 40% | ||
| 22 | 1 b | Hb 194 g/L | Hb 86 g/L | 56 |
| 23 | (1) c | Severe polycythemia day 1 | ||
| 24 | 1 | Hb 259 g/L | Hb 52 g/L | 80 |
| 25 | 1 | Hb 171 g/L | Hb 123 g/L | 28 |
| 30 | 0 | Normal | ||
| 31 | 1 | Hb 163 g/L | Hb 172 g/L | 5 |
| 33 | 1 | Hct 77% | ||
| 34 | 0 | Normal | Normal | |
| 35 | 1 | Hb 268 g/L; Hct 78% | Hb 115 g/L; Hct 38% | 20 |
| 36 | 1 | Hb 244 g/L; Hct 0.75% |
a Polycythemia defined as >95th percentile ; 0 = no; 1 = yes;
c Not included in analysis because no exact values for hemoglobin or hematocrit reported.
Cases from literature
There are 18 previous case reports of limb reductions in TTTS, 2 of which are included in our series (cases 2 and 13), and the other 16 cases are documented in Table 4 . TTTS stage was reported or could be deduced from the publication or from additional information provided by the authors in all but 1 case (case 24), which was likely stage I.
| Patient | Study | Twin-twin transfusion syndrome diagnosis | Affected twin | Affected limb | Location of injury | Fetal therapy | Timing of diagnosis of limb defect | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Gestational age, wk | Stage | Side | Extent a | Description | ||||||
| 21 | Carr et al | 17 | III | R | LL | Right | 1 | L (+5A) b | Postnatal (26 wk) | |
| 22 | Ballard et al | 17 | IIIR | D | UL | Left | — | Distal arm | L | Postnatal (28 wk) |
| 23 | Cincotta et al | 26 | IIID + IIIR | R | LL | Left | 0 | Ischemic toes | A | Postnatal |
| 24 | Dawkins et al | 23 | Oligohydramnios/polyhydramnios sequence; Doppler findings not reported | R | LL | Left | 0 | Foot, including heel | A (6 times) | Postnatal (32 wk) |
| 25 | Dickinson and Evans | — | III | R | LL | Right | 0 | Below knee | A (4 times) | Postnatal (27 wk) |
| 26 | — | II | R | LL | Left | 0 | Below knee | A (3 times) | Postnatal (32 wk) | |
| 27 | Fox et al | 20 | IIID + IIIR | R | LL | Right | 1 | Midthigh | A (7 times) | Ultrasound after amnioreduction (32 wk) |
| 28 | 20 | I | R | LL | Left | 0 | Skin only | A (5 times) | Postnatal (27 wk) | |
| 29 | Gilbert et al | 24 | V | R | LL | Right | 1 | Below inguinal canal, dissecting intramural hematoma in femoral artery | None | Postnatal (24 wk) |
| 30 | Lopriore et al | 16 | II | R | UL | Right | — | Hand | L | Ultrasound scan after laser therapy (24 wk) |
| 31 | 18 | I | R | UL | Right | — | Lower arm | L | Postnatal (32 wk) | |
| 32 | Lundvall et al | 17 | IV | R | LL | Right | 1 | Level of ligamentum inguinale thrombus right common iliac artery | L | Ultrasound scan after laser therapy (21 wk) |
| 33 | Margono et al | 28 | V | R | LL | Right | 0 | Foot | None | Postnatal (30 wk) |
| 34 | Nagai et al | 27 | IIIR | R | LL | Right | 0 c | Marked atrophy/dense blackened necrosis from superior pole of patella to the tips of all 5 toes | None | Postnatal (27 wk) |
| 35 | Scott and Evans | 24 | Progressed into stage IIID at 31 wk | R | LL | Left | 0 | Lower leg/foot | A (3 times) | Postnatal (32 wk) |
| 36 | Watkins et al | 27 | IIIR | R | LL | Left | 0 | None | Postnatal (29 wk) | |
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