Objective
The purpose of this study was to compare perinatal outcomes of pregnancies that undergo “early” (<17 weeks’ gestation) or “late” (>26 weeks’ gestation) fetoscopic laser ablation of placental vascular anastomoses for twin-twin transfusion syndrome (TTTS) with “conventional” cases that were treated at 17-26 weeks’ gestation.
Study Design
We conducted a single center, retrospective analysis of 325 consecutive pregnancies that underwent fetoscopic laser therapy for severe TTTS.
Results
Twenty-four “early,” 18 “late,” and 283 “conventional” pregnancies with severe TTTS underwent laser therapy. Fetoscopy duration, gestation at delivery, survival rate, and complications were comparable among groups, except for preterm premature rupture of membranes at <7 days after laser therapy, which was more common in the “early” group than in either of the other 2 groups.
Conclusion
Laser therapy for TTTS at <17 or >26 weeks’ gestation has similar outcomes to procedures done at 17-26 weeks’ gestation. We suggest that conventional gestational age guidelines of 16-26 weeks for laser therapy for TTTS should be reevaluated.
Twin-twin transfusion syndrome (TTTS) complicates 10-15% of monochorionic/diamniotic twin pregnancies. This syndrome results from unbalanced blood flow through placental vascular anastomoses that results in an hypovolemic, oliguric donor twin with oligoanhydramnios and an hypervolemic, polyuric recipient twin with polyhydramnios. If untreated, mortality rates exceed 90%, and approximately 30% of survivors may show neurodevelopmental impairment.
For Editors’ Commentary, see Contents
See related editorial, page 165
In 2004, a randomized controlled trial demonstrated that fetoscopic laser ablation of placental anastomoses in TTTS resulted in better perinatal outcomes than serial amnioreduction. Only pregnancies at 16-26 weeks’ gestation were included in this trial. Part of the rationale for these gestational age limits was that fetoscopic laser ablation at <16 weeks may be more challenging, because the amnion and chorion may not have yet fused. After 26 weeks’ gestation, it was felt that more traditional approaches (such as expectant management, serial amnioreduction, or preterm delivery) were preferred. As is common practice in the first randomized trial that evaluates any new therapy, stringent inclusion and exclusion criteria were set. These trial criteria have been adopted by the Food and Drug Administration (FDA) in the United States, which, under the Humanitarian Device Exemption Program, permits fetoscopic equipment to “be used for the treatment of TTTS for fetuses whose gestational age is between 16 and 26 weeks.” In the United States, any fetoscopic procedure outside of these limits can proceed only by special exemption from the FDA.
Extremely premature birth is associated with major long-term handicaps that include cerebral palsy, mental retardation, and/or hearing, visual, and respiratory impairment. Because these fetuses also experience morbidity that is related to TTTS per se (abnormal Doppler results, hydrops, anemia, polycythemia, and renal and cardiac dysfunction ), preterm delivery carries a high risk of significant neonatal morbidity and death, compared with age-matched control subjects, especially at <29 weeks’ gestation.
Although TTTS most commonly occurs during the second trimester of pregnancy, it can develop at <16 and >26 weeks’ gestation. Reports of perinatal outcomes after early and late laser procedures are sparse. The aim of our study was to report on pre- and postnatal characteristics and perinatal outcome of early and late laser procedures and to compare these with procedures that were performed within the more conventional range of 17–26 weeks’ gestation.
Materials and Methods
We conducted a retrospective chart review of all consecutive monochorionic/diamniotic twin pregnancies that were complicated by severe TTTS and had been treated with fetoscopic laser ablation of vascular anastomoses at Mount Sinai Hospital, Toronto, Ontario, Canada (a regional/national referral center for fetoscopy) between January 1999 and April 2012. Exclusion criteria were triplets, fetal death at first presentation, and fetal chromosomal or congenital abnormalities. The study was approved by the Research Ethics Board of the hospital (MSH REB #12-0190-C).
TTTS was diagnosed with standard ultrasound criteria that included oligohydramnios (deepest vertical pool, <2 cm) in the donor and polyhydramnios (deepest vertical pool, >8 cm at <20 weeks’ gestation or >10 cm at >20 weeks’ gestation) in the recipient twin. Staging was performed according to Quintero et al (in stage III, the suffix “R” is used when the recipient is affected, and “D” when the donor is affected). Cases were divided into 3 groups based on the timing of the laser procedure: (1) “early,” <17 weeks’ gestation, (2) “conventional,” 17-26 weeks’ gestation; or (3) “late,” >26 weeks’ gestation. For the early group, a cutoff of 17 weeks was chosen to allow sufficient power for statistical analysis. Eight cases at <16 weeks’ gestation will be described separately.
Selective laser ablation of placental anastomoses was performed as previously described. Most procedures were performed with local maternal anesthesia (Xylocaine; AstraZeneca, London, UK) with intravenous sedation (remifentanil ± propofol; n = 292 cases); a few cases, during our initial experience, were performed with general (n = 16 cases) or regional (n = 17 cases) anesthesia. A 2-mm 0-degree fetoscope and 3.7-mm (11F) operating sheath (Karl Storz GmbH, Tüttlingen, Germany) and a 600 μ Nd:YAG laser fiber (Surgical Laser Technologies Inc, Montgomeryville, PA) were introduced through a 12F operating sheath (Cook Medical Inc, Bloomington, IN) that had been inserted directly with the use of a trochar under continuous ultrasound guidance. Thirty- and 70-degree fetoscopes and a curved operating sheath were used, as necessary, for the visualization of anterior placentas. In 1 case of TTTS at 16.1 weeks’ gestation with a completely anterior placenta, 900 mL of warmed NaCl 0.9% were first infused into the recipient’s sac through a 20-G needle. This amnioinfusion created a safe “window” so that transplacental trochar passage could be avoided.
Intertwin placental vascular anastomoses were identified, and all were ablated selectively along the vascular equator. Amnioinfusion was used as necessary, and, at the end of the procedure, amnioreduction was performed to leave the deepest amniotic fluid pool in the normal range. Prophylactic tocolytics (indomethacin [rectally] and nifedipine [orally]) and antibiotics (cefazolin [intravenously]) were administered routinely.
After the laser procedures, patients were kept for 1 night in the hospital and discharged the next morning; follow-up evaluation was performed at Mount Sinai, or the patient was referred back to their local regional perinatal center for follow-up evaluation. Details regarding pregnancy and neonatal outcomes were obtained from hospital records, patients, and/or referring physicians.
Demographics, TTTS stage, perioperative characteristics, complications, and maternal and neonatal outcomes were recorded. “Major” maternal complications were defined as (1) intensive care unit admission, (2) pulmonary edema, (3) “mirror” syndrome, or (4) hemorrhage (per vagina or intraperitoneally) that required blood transfusion.
Categoric variables were compared among the 3 groups by the Pearson χ 2 test (or the Fisher exact test as indicated). For continuous variables, medians were compared by the Wilcoxon-Mann-Whitney test. A probability value of < .05 was considered statistically significant. Statistical analyses were performed with STATA software (version 11; Stata Corporation, College Station, TX).
Results
In the 13-year study period, 325 cases of severe TTTS were treated with fetoscopic selective laser ablation of the placental anastomoses. Twenty-four cases (7.4%) underwent “early” laser therapy; 283 cases (87.1%) underwent “conventional” laser therapy, and 18 cases (5.5%) underwent “late” laser therapy. Demographics, laser therapy data and complications, TTTS stage, and neonatal outcomes are shown in Table 1 . Maternal characteristics, year of laser procedure, and placental location were similar in all groups.
| Variable | Laser therapy timing | ||||
|---|---|---|---|---|---|
| “Conventional” | “Early” | P value | “Late” | P value | |
| Maternal characteristics | |||||
| Age, y a | 31 (18–47) | 31 (20–41) | .988 | 30 (22–38) | .398 |
| Nulliparity, n (%) | 109 (41.3%) | 9 (45%) | .816 | 5 (31.3%) | .602 |
| Laser therapy characteristics | |||||
| Anterior placenta | 126 (44.5) | 9 (37.5) | .53 | 7 (38.9) | .808 |
| Gestational age at surgery, wk a | 21 (17.1–25.6) | 16 (14.6–17.0) | < .001 | 27.1 (26.1–30.3) | < .001 |
| Cervical length, mm b | 36 ± 10 | 37 ± 7 | .334 | 31 ± 12 | .09 |
| Cerclage, n (%) | 24 (8.5) | 1 (4.2) | .706 | 2 (11.1) | .661 |
| Length of surgery, min a | 57 (19–180) | 53 (25–145) | .505 | 58 (30–142) | .845 |
| Twin-twin transfusion syndrome stage, n (%) | |||||
| I | 13 (4.6) | — | .034 | 1 (5.6) | .686 |
| II | 92 (32.5) | 6 (25.0) | .034 | 4 (22.2) | .686 |
| III | 151 (53.4) | 16 (66.7) | .034 | 7 (38.9) | .686 |
| IV | 27 (9.5) | 2 (8.3) | .034 | 6 (33.3) | .686 |
| III and IV | 178 (62.9) | 18 (75.0) | .275 | 13 (72.2) | .615 |
| Laser therapy complication, n (%) | |||||
| Preterm premature rupture of membranes after laser therapy | |||||
| <7 d | 18 (6.4) | 6 (25.0) | .006 | 1 (5.6) | 1 |
| <32 wk | 180 (63.7) | 14 (58.3) | .661 | 10 (55.5) | .327 |
| Preterm labor after laser therapy | |||||
| <7 d | 32 (11.3) | 1 (4.2) | .491 | 2 (11.1) | 1 |
| <28 d | 56 (19.8) | 1 (4.2) | .059 | 5 (27.8) | .378 |
| Major maternal complication | 14 (5.0) | 2 (8.3) | .361 | — | 1 |
| Any maternal complication | 25 (8.8) | 3 (12.5) | .469 | 2 (11.1) | .669 |
| Mode of delivery, n (%) | |||||
| Vaginal/vaginal | 152 (53.7) | 13 (54.2) | .66 | 8 (44.4) | .12 |
| Vaginal/cesarean | 3 (1.1) | — | 1 (5.6) | ||
| Cesarean | 108 (38.2) | 8 (6.9) | 6 (33.3) | ||
| Unknown | 20 (7.1) | 3 (12.5) | 3 (16.7) | ||
| Obstetric outcome | |||||
| Preterm labor | |||||
| <32 wk gestation, n (%) | 142 (50.2) | 14 (58.3) | .526 | 5 (27.8) | .088 |
| <28 wk gestation, n (%) | 78 (27.6) | 7 (29.2) | .817 | 3 (16.7) | .417 |
| Gestational age at delivery, wk b | 31 ± 5 | 30 ± 4 | .482 | 33 ± 3 | .076 |
| Laser-delivery interval, wk a | 10 (0–22) | 14 (0.4–19) | < .001 | 6 (0.1–10) | .005 |
| Neonatal outcome | |||||
| At least 1 survivor, n (%) | 246 (86.9) | 20 (83.8) | .542 | 17 (94.4) | .711 |
| Dual survivors, n (%) | 160 (56.6) | 13 (56.5) | 1 | 14 (77.8) | .089 |
| No survivor, n (%) | 37 (13.2) | 4 (16.7) | .542 | 1 (5.6) | .711 |
| Donor survivor, n (%) | 188 (66.4) | 15 (62.5) | .823 | 15 (83.3) | .195 |
| Recipient survivor, n (%) | 218 (77.0) | 19 (78.3) | 1 | 16 (88.9) | .381 |
| Neonatal death <7 d after birth, n/N (%) | 30/406 (7.4) | 3/34 (8.8) | .733 | 1/31 (3.1) | .716 |
| Donor weight at delivery, g a | 1372 (43–3657) | 1352 (485–2778) | .916 | 1498 (480–2495) | .511 |
| Recipient weight at delivery, g a | 1668 (160–3835) | 1537 (160–2975) | .443 | 1822 (880–2550) | .433 |
| Year of laser therapy, n (%) | |||||
| ≤2005 | 100 (35.3) | 10 (41.7) | .516 | 3 (16.7) | .128 |
| ≥2006 | 183 (64.7) | 14 (58.3) | 15 (83.3) | ||
a Data are given as median (range);
Early vs conventional laser therapy
TTTS stage, duration of surgery, and need for cerclage were similar in both groups. Although the rate of preterm premature rupture of the membranes (PPROM) at <32 weeks’ gestation was similar between groups, there were more cases of PPROM within 7 days of laser surgery in the early group; there were, however, no differences in the rate of preterm delivery within 7 days, <28 weeks’ gestation, or <32 weeks’ gestation. Laser therapy to delivery interval was longer in early, compared with conventional, cases; the gestational age at delivery was similar in both groups. There were no significant differences in survival at either 7 or 30 days of life for 1 or both fetuses, in neonatal deaths within 7 days of birth, in mode of delivery, or in birthweight between early and conventional cases. There were no differences in maternal complications between the groups (8.3% vs 5%; P = .361).
Table 2 summarizes the 8 cases that were treated with laser therapy at <16 weeks gestation (range, 14.6–15.6 weeks’ gestation). All but 1 case were stage III; 1 case had needed a previous amnioinfusion to create an amniotic fluid “window” to allow safe trochar insertion to avoid the placenta. Three of 8 cases (38%) were complicated by PPROM within 7 days of the laser therapy. Of 16 fetuses, 11 (69%) were born alive and thrived. Two donors, both with absent end-diastolic velocity in the umbilical artery, and 1 donor with reverse A waves in the ductus venosus died within 24 hours of the laser therapy. In 1 case of postoperative twin-anemia-polycythemia syndrome, the recipient who was transfused in utero (hemoglobin level, 36 g/L) at 20 weeks’ gestation died 2 days later; when the patient went into spontaneous labor at 24 weeks’ gestation, the donor was noted to be dead on admission (birthweight, 485 g). Finally, one patient ( Table 2 ; case 7) had an emergency cesarean section for preterm labor at 26.3 weeks’ gestation; the birthweights were 810 g and 490 g, respectively, for recipient and donor. The donor died from complications of extreme prematurity and low birthweight; the recipient survived.
| Case | Gestational age at laser therapy, wk | Twin-twin transfusion syndrome stage | Placental position | Length of surgery, min | Preterm premature rupture of membranes within 7 d | Gestational age at delivery, wk | Adverse outcome | |
|---|---|---|---|---|---|---|---|---|
| Recipient (R) | Donor (D) | |||||||
| 1 | 14.6 | III R | Anterior | 48 | No | 32.6 | — | — |
| 2 | 14.6 | III R+D | Anterior | 41 | Yes | 32.3 | — | — |
| 3 | 15.1 | III R | Posterior | 28 | No | 24.1 | Intrauterine fetal death at 20 weeks’ gestation | Intrauterine fetal death at 24 weeks’ gestation |
| 4 | 15.1 | III R+D | Anterior | 38 | Yes | 28.1 | — | Intrauterine fetal death after laser therapy |
| 5 | 15.5 | III D | Posterior | 38 | Yes | 30.1 | — | Intrauterine fetal death after laser therapy |
| 6 | 15.5 | III R | Anterior | 30 | No | 33.1 | — | — |
| 7 | 15.6 | III D | Posterior | 38 | No | 26.3 | — | Neonatal death (490 g) |
| 8 | 15.6 | II | Posterior | 38 | No | 32.6 | — | — |
Late vs conventional laser therapy
TTTS stage was significantly higher in late cases compared with conventional cases ( Table 1 ). Indeed, one-third of the recipients were hydropic (stage IV) in the late group, compared with 9.5% in the conventional group ( P = .034). There were no differences in either the duration or technical difficulty of laser surgery or in the rate of postoperative complications. Women in the late group delivered later than those in the conventional group; however, the laser therapy–to-delivery interval was significantly shorter in late cases compared with conventional cases, although the mean interval in the late group was 6 weeks.
Despite late cases presenting at a more advanced stage of TTTS, survival of at least 1 fetus and dual survival were higher in the late group compared with the conventional group. There were no significant differences in birthweight between late and conventional cases. There were no significant maternal complications in the late laser therapy group.
The 18 patients in the late group are detailed in Table 3 . PPROM within 7 days of laser therapy occurred only once. One neonate from the late group died in its first week of life. Two donors (both with stage IV TTTS) died in utero within 24 hours of the laser therapy. In case 4, the prolonged duration of the procedure (142 minutes) was related to closely approximated placental cord insertions and intraamniotic bleeding that necessitated an amnio exchange of 20 L. The recipient died within 24 hours of the procedure, probably of acute severe anemia. A massive grade IV intraventricular hemorrhage was detected in the donor. Labor was induced 6 days after laser therapy with a plan for palliative care, and the neonate died shortly after birth. Finally, in 1 case who underwent surgery at 26.6 weeks gestation for stage IV TTTS, the recipient died unexpectedly 7 weeks after laser therapy. Otherwise, 83.3% of the babies (30/36) were born alive and had an uneventful neonatal course.
