Thirty-six patients were managed conservatively with a mean of 4.2 ± 2.1 ultrasound evaluations. Twenty-seven (75.0%) patients returned to their referring hospital when a sonogram identified no evidence of progression. Ten cases were excluded due to a lack of sufficient perinatal data (three cases) or loss to follow-up (seven cases). Of the remaining 17 patients, five regressed, three remained at Stage I, three experienced spontaneous abortion, and six cases progressing in stage underwent pregnancy termination. Nine patients were followed until delivery at the study hospital. Two patients experienced spontaneous abortion within a week after diagnosis. The seven cases that progressed did this to Stage 2 (n = 2), Stage 3 (n = 2), and Stage 4 (n = 3). Eventually, 26 cases of EM were analyzed. Thirteen patients (50%) advanced in Stage, 5 (19.2%) experienced spontaneous abortion, 5 (19.2%) regressed, and three (12.5%) remained at Stage I (Fig. 4). Of the 13 patients who advanced in stage, two advanced to Stage II, five advanced to Stage III, four advanced to Stage IV, and two advanced to Stage V.
Three of the 13 patients underwent laser surgery after advancing to Stage II (n = 2) and III (n = 1), and the other 10 patients requested pregnancy termination.
Of the 35 patients in the AR group, 21 cases were diagnosed prior to 26 weeks of gestation and 14 cases were diagnosed after 26 weeks of gestation. Among 21 cases, eight (38.1%) underwent two or more procedures; of these, four (19%) underwent FLOC due to progression in stage after two to four ARs. The pregnancy outcomes of these four patients were as follows: one case of double intrauterine death at Day 1 post-FLOC, two cases of single intrauterine death within 7 days post-FLOC, and one case of delivery at 35 weeks with dual survivors. Six patients (42.9%) underwent more than two ARs among 14 cases with GA at diagnosis of ≥26 weeks.
Of the 28 patients in the FLOC group, one was offered cerclage placement at the time of FLOC with CL = 1.3 cm and delivered at 32 weeks of gestation with the survival of both twins. One patient with CL = 0.6 cm experienced preterm premature rupture of membranes (PPROM) 16 days after FLOC and cerclage placement.
There were significant differences in recipient MVP, GA at diagnosis, the number of days from diagnosis to delivery, and GA at delivery among the three groups (all P < 0.05). The GA at diagnosis was higher in the AR group (25.9 ± 2.3 weeks) than in the FLOC group (22.3 ± 2.3 weeks) and the EM group (22.4 ± 2.5 weeks) (P < 0.001). The GA at delivery was higher in the FLOC group (33.4 ± 4.3 weeks) than in the AR group (30.6 ± 3.7 weeks) and the EM group (29.1 ± 5.5 weeks) (P = 0.002). The median number of days from diagnosis to delivery was 33 (12–84) in the EM group, 34 (11–56) in the AR group, and 91 (45–110) in the FLOC group (P < 0.001) (Table 1), which that in FLOC group was longer than AR and EM group. No differences were found among the three groups in terms of maternal age, nulliparity, receipt of ART, coexisting sIUGR or CL.
Subjects with poor outcomes accounted for 17.9% of the FLOC group and 17.1% of the AR group; both of these percentages were lower than 61.5% of the EM group (P = 0.002). The perinatal survival rates of two survivors to 28 days of age in the EM, AR, and FLOC groups were 30.8%, 77.1%, and 71.4%, respectively. The incidence rates of no survivors in the three groups were 61.5%, 17.1%, and 10.7%, respectively. The perinatal survival rates of at least one survivor in the three groups were 38.5%, 82.9%, and 89.3%, respectively (P < 0.001) (Table 2).
Compared with the patients in the EM group, those in the AR and FLOC groups had a lower risk of poor outcomes [OR = 0.14, 95% confidence interval (CI), 0.04–0.47; and OR = 0.14, 95% CI, 0.04–0.51, respectively]. After adjustments for maternal age, nulliparity, recipient MVP, coexisting sIUGR, CL, placenta location, and GA at diagnosis, the subjects in the AR group (OR = 0.20, 95% CI, 0.04–0.98) and FLOC group (OR = 0.09, 95% CI, 0.02–0.40) had a lower risk of poor outcomes than those in the EM group (Table 3). In addition, the crude OR of no survivors was 0.11 (95% CI, 0.03–0.38) for the AR group and 0.08 (95% CI, 0.02–0.33) for the FLOC group. The corresponding adjusted ORs were 0.20 (95% CI, 0.04–0.95) and 0.04 (95% CI, 0.01–0.25) after adjusting for the above covariates (Table 3).
Further comparisons of pregnancy outcomes and complications between the FLOC and AR groups with GA at diagnosis of <26 weeks revealed that interval days from operation to delivery was longer in the FLOC group than AR group (P < 0.001). The incidences of spontaneous abortion and pregnancy loss within 1 week after the procedure were similar for the two groups. The incidence of PPROM within 4 weeks after the procedure was lower in the FLOC group (7.1%) than in the AR group (33.3%) (P = 0.028). Three patients (14.3%) suffered recurrent symptoms of polyhydramnios and one patient (4.8%) was complicated with intrauterine infection in the AR group, but none in the FLOC group (Table 4).
In this single but major referral-center study, we focused on the natural history and describe the outcomes of Stage I TTTS patients treated with three initial management strategies including EM, AR, or FLOC. Progression in stage or pregnancy termination occurred in approximately two-thirds of cases that were managed expectantly as an initial strategy, which was the leading cause of considerable fetal mortality and poor pregnancy outcome in this study, whereas intervention was associated with better pregnancy outcomes and an improved perinatal survival rate compared to EM.
A 50% rate of progression among Stage I patients in this study was identical to 50% of Duryea et al.'s study11 but lower than 60% reported by Emery et al. Other studies have reported varying rates of progression in Stage I TTTS, from 10%12 to 45%.13,14 The lower incidence of progression may be an effect of AR, as some patients underwent AR prior to EM.15 In two subsequent studies8,11 and our study, which had a much higher incidence of progression, any intervention was not implemented in EM group; thus, this group could reflect the natural course of Stage I disease and may provide a more accurate incidence of progression.
Both AR and FLOC therapy may decrease the risk of poor pregnancy outcomes and improve the perinatal survival rate compared to EM. Multivariate analysis suggested that FLOC therapy and AR were associated with reduced risks of poor pregnancy outcomes (OR = 0.09; 95% CI, 0.02–0.40 and OR = 0.20; 95% CI, 0.04–0.98, respectively) and of no survivors to 28 days of age after birth (OR = 0.04; 95% CI, 0.01–0.25 and OR = 0.20; 95% CI, 0.04–0.95, respectively) compared with EM. As with any observational analysis, this study does not certify causal inferences because many other potential confounding factors, such as family economic conditions, regular perinatal care, were not included. However, the much lower adjusted OR of poor pregnancy outcomes and no perinatal survivors indicated that the protective effect of FLOC was strong. Any confounders that could lead to such a strong association should have an even stronger protective effect, yet we identified no such confounders in the literature. Notably, clinical symptoms and recipient MVP, which may predict poor outcomes, tended to be more severe in the AR and FLOC groups than in the EM group.
The mechanism of TTTS is unbalanced transfusion from the donor to the recipient, mediated at least in part by arteriovenous anastomoses within the placenta. The presence of arteriovenous anastomoses without a compensating anastomosis between pairs of arteries has been suggested to indicate a higher risk for the development of TTTS.16 Fetoscopic laser coagulation of anastomotic vessels on the chorionic plate aims to correct what is known about the pathophysiology of the syndrome and to dichorionize a monochorionic placenta.17 The injection of monochorionic placentas with a dye after laser surgery showed that in the etiology of TTTS, vascular anastomosis could be eliminated by ablating the placental vascular anastomosis.18
AR is hypothesized to decrease intraamniotic and placental intravascular pressure and increase uterine artery blood flow, potentially facilitating placental blood flow and/or reducing the incidence of preterm labor related to polyhydramnios. However, in view of the inability to resolve the etiology of TTTS, the recurrence of polyhydramnios is inevitable, and repeated invasive procedures increase the likelihood of complications such as PPROM, preterm delivery, vaginal bleeding and/or abruption, and chorioamnionitis.19 These factors may explain the higher rate of PPROM within 4 weeks and the shorter interval from operation to delivery in the AR group compared with the FLOC group. This is also the reason why 18 (51.4%) cases underwent two or more AR and the rates of infection were 4.8% in AR group whereas there were no infection cases in FLOC group.
Comparing previous cohorts,12,20 this study is the largest retrospective review of stage I cases to date (n = 89) among single-center studies to date and the first study to investigate the management strategy and corresponding outcomes for Stage I TTTS in China. In view of the possible selection bias inherent to the retrospective nature of this study, our study has several limitations. First, more patients in the EM group than in the FLOC and AR groups had missing data for the outcomes of interests, which may compromise the between-group comparability and, therefore, introduce bias. However, for patients whose initial treatment strategy was EM, we did not identify any material difference between patients who did and did not remain in the analysis. Additionally, the prognoses of patients in the EM group and the between-group differences regarding the outcomes of interest in our study were highly consistent with previous studies with a rigorous design and more complete data. Second, although our center is a major referral center for TTTS in Northern China, and the patients involved in the study were referred from most of the northern provinces, this single-center, hospital-based study may still allow for selection bias. Additionally, in our study, the cardiac function of twins was not assessed at the time of diagnosis or after treatment. The prognosis of TTTS is closely related to the Quintero stage and fetal cardiac function.21 The current study indicates that the Tei index is appropriate for assessing the severity of cardiac function in early-stage TTTS (I and II).22 Some centers have considered TTTS cardiomyopathy when making treatment recommendations regarding Quintero Stage I and II fetuses.
Green-top Guideline November 2016 of Management of Monochorionic Twin Pregnancy composed by the Royal College of Obstetricians and Gynaecologists supported that Quintero Stage I under specific circumstances should be treated with FLOC in accordance with the protocol in our center. In addition, Wagner et al.'s study followed up a cohort of 20 Stage I TTTS and considered that a long-term outcome in Stage I TTTS was better after laser surgery than with conservative management.20 Roberts et al. had a review including three studies (253 women and 506 babies) to evaluate the impact of treatment modalities in TTTS. Their conclusions were that endoscopic laser coagulation of anastomotic vessels should continue to be considered in the treatment of all stages of TTTS to improve neurodevelopmental outcomes.23 In view that FLOC is the only therapy that directly halts the pathologic process and improved substantially a poor outcome and worse prognosis, it is reasonable to use FLOC for Stage I TTTS unless a randomized clinical trial reveals marked disadvantages associated with FLOC. At present, randomized controlled trial comparing a conservative management and laser surgery (TTTS1) had been conducted since 2011 with clinical Trials.gov Identifier: NCT01220011. This trial may answer an important question and help in the management and tailoring of surgical indications in Stage I TTTS.
Despite these limitations in this study, our results showed that both AR and laser therapy could decrease the risk of poor pregnancy outcomes and improve the perinatal survival rate and FLOC therapy may be more effective in cases of Stage I TTTS diagnosed before 26 weeks of gestation. Further study is needed to execute the risk stratification integrating more comprehensive indexes including fetal heart function, CL, and placental arteries anastomosis. And besides, whether it is possible to consider FLOC as a first-line treatment for Stage I TTTS prior to 26 weeks of gestation need to be further confirmed in settings where laser ablation expertise is available for Chinese populations.
The authors thank all the clinicians of the Obstetrics & Gynecology Department of Peking University Third Hospital for their excellent assistance.
This work was supported by grants from the National Key R&D Program of China (2016YFC1000408).
Jing Yang and Peng-Bo Yuan contributed to the data analysis and manuscript drafting. Yuan Wei and Hong-Tian Li participated in revising the article. Xue-Ju Wang and Jing Wang participated in the acquisition of data. Yuan-Hui Jiang, Xiao-Li Gong, and Lu-Yao Li participated in execution. Yang-Yu Zhao contributed to conception or study design and final approval of the version to be published.
Conflicts of Interest
. Baschat A, Chmait RH, Deprest J, et al Twin-to-twin transfusion syndrome
(TTTS). J Perinat Med 2011;39(2):107–112. doi: 10.1515/JPM.2010.147.
. Cincotta RB, Gray PH, Phythian G, et al Long term outcome of twin-twin transfusion syndrome. Arch Dis Child Fetal Neonatal Ed 2000;83(3):F171–F176. doi: 10.1136/fn.83.3.f171.
. Walsh CA, Mcauliffe FM. Recurrent twin-twin transfusion syndrome after selective fetoscopic laser photocoagulation: a systematic review of the literature. Ultrasound Obstet Gynecol 2012;40(5):506–512. doi: 10.1002/uog.11105.
. Haverkamp F, Lex C, Hanisch C, et al Neurodevelopmental risks in twin-to-twin transfusion syndrome
: preliminary findings. Eur J Paediatr Neurol 2001;5(1):21–27. doi: 10.1053/ejpn.2001.0400.
. Simpson LL. Twin-twin transfusion syndrome. Am J Obstet Gynecol 2013;208(1):3–18. doi: 10.1016/j.ajog.2012.10.880.
. Khalil A, Cooper E, Townsend R, et al Evolution of stage I twin-to-twin transfusion syndrome
(TTTS): systematic review and meta-analysis. Twin Res Hum Genet 2016;19(3):207–216. doi: 10.1017/thg.2016.33.
. Management of monochorionic twin pregnancy: green-top guideline no. 51. BJOG 2017;124(1):e1–e45. doi: 10.1111/1471-0528.14188.
. Emery SP, Hasley SK, Catov JM, et al North American fetal therapy network: intervention vs expectant management for stage I twin-twin transfusion syndrome. Am J Obstet Gynecol 2016;215(3). 346.e1-.e7. doi: 10.1016/j.ajog.2016.04.024.
. Sago H, Ishii K, Sugibayashi R, et al Fetoscopic laser photocoagulation for twin-twin transfusion syndrome. J Obstet Gynaecol Res 2018;44(5):831–839. doi: 10.1111/jog.13600.
. Quintero RA, Morales WJ, Allen MH, et al Staging of twin-twin transfusion syndrome. J Perinatol 1999;19(8 Pt 1):550–555. doi: 10.1038/sj.jp.7200292.
. Duryea EL, Happe SK, Mcintire DD, et al The natural history of twin-twin transfusion syndrome stratified by Quintero stage. J Matern Fetal Neonatal Med 2016;29(21):3411–3415. doi: 10.3109/14767058.2015.1131263.
. Bebbington MW, Tiblad E, Huesler-Charles M, et al Outcomes in a cohort of patients with stage I twin-to-twin transfusion syndrome
. Ultrasound Obstet Gynecol 2010;36(1):48–51. doi: 10.1002/uog.7612.
. Washburn EE, Sparks TN, Gosnell KA, et al Stage I twin-twin transfusion syndrome: outcomes of expectant management and prognostic features. Am J Perinatol 2018;35(14):1352–1357. doi: 10.1055/s-0038-1627095.
. Dickinson JE, Evans SF. The progression of disease stage in twin-twin transfusion syndrome. J Matern Fetal Neonatal Med 2004;16(2):95–101. doi: 10.1080/14767050400004692.
. Sueters M, Oepkes D. Diagnosis of twin-to-twin transfusion syndrome
, selective fetal growth restriction, twin anaemia-polycythaemia sequence, and twin reversed arterial perfusion sequence. Best Pract Res Clin Obstet Gynaecol 2014;28(2):215–226. doi: 10.1016/j.bpobgyn.2013.12.002.
. Denbow ML, Cox P, Taylor M, et al Placental angioarchitecture in monochorionic twin pregnancies: relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Am J Obstet Gynecol 2000;182(2):417–426. doi: 10.1016/s0002-9378(00)70233-x.
. Chalouhi GE, Deloison B, Ville Y. Management of twin-to-twin transfusion syndrome
. Gynecol Obstet Fertil 2012;40(3):174–181. doi: 10.1016/j.gyobfe.2012.01.009.
. Lopriore E, Slaghekke F, Middeldorp JM, et al Residual anastomoses in twin-to-twin transfusion syndrome
treated with selective fetoscopic laser surgery: localization, size, and consequences. Am J Obstet Gynecol 2009;201(1). 66.e1-e4. doi: 10.1016/j.ajog.2009.01.010.
. Crombleholme TM, Shera D, Lee H, et al A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment
of severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2007;197(4):396.e19. doi: 10.1016/j.ajog.2007.07.020.
. Wagner MM, Lopriore E, Klumper FJ, et al Short- and long-term outcome in stage I twin-to-twin transfusion syndrome
treated with laser surgery compared with conservative management. Am J Obstet Gynecol 2009;201(3). 286.e1-e6. doi: 10.1016/j.ajog.2009.05.034.
. Lewi L, Devlieger R, De Catte L, et al Twin-twin transfusion syndrome: the good news is; there is still room for improvement. Acta Obstet Gynecol Scand 2012;91(10):1131–1133. doi: 10.1111/aogs.12002.
. Villa CR, Habli M, Votava-Smith JK, et al Assessment of fetal cardiomyopathy in early-stage twin-twin transfusion syndrome: comparison between commonly reported cardiovascular assessment scores. Ultrasound Obstet Gynecol 2014;43(6):646–651. doi: 10.1002/uog.13231.
. Roberts D, Neilson JP, Kilby MD, et al Interventions for the treatment
of twin-twin transfusion syndrome. Cochrane Database Syst Rev 2014;(1):Cd002073. doi: 10.1002/14651858.CD002073.pub3.
Keywords:© 2019 by Lippincott Williams & Wilkins, Inc.
Treatment; Twin-to-twin transfusion syndrome; Quintero stage I