Collaboration on Treatment of Twin-to-Twin Transfusion Syndrome in a Borderless Nordic Center Open Access

Monochorionic (MC) multiple pregnancies are associated with an increased risk of specific complications due to the shared placenta and the placental vascular anastomoses [1]. About 15% of MC pregnancies are complicated by twin-to-twin transfusion syndrome (TTTS) and 5% by spontaneous twin-anemia polycythemia sequence (TAPS). The cause of these complications is the unequal distribution of blood supply through the vascular anastomoses [1‒3].

Fetoscopic laser photocoagulation (FLP) is a minimally invasive procedure for treating TTTS [4, 5]. The surgical techniques most used are selective laser photocoagulation of communicating vessels (SLPCVs) and its modified version, the sequential selective laser coagulation, both of which were suggested by Quintero et al. [6, 7]. The Solomon technique [8, 9] is a newer technique that in a randomized trial demonstrated better outcomes in enhancing survival and reducing the rate of TTTS recurrence and post-laser TAPS [10, 11]. However, the absolute risk of residual anastomoses has been reported to be lower in other series without solomonization [12] and a recently published systematic review [13] has suggested that this technique may be associated with a higher risk of placental abruption and earlier gestational age (GA) at delivery than SLPCV.

TTTS cases are often complicated by coexisting TAPS or selective fetal growth restriction (sFGR). A recent study has shown that TAPS accompanied 15% of TTTS cases before FLP. Perinatal mortality and morbidity were expected to be lower in the TTTS-only group than in the TTTS + TAPS group. However, the results showed the opposite [14]. About 60% of TTTS cases are complicated by sFGR prior to laser surgery. Those cases are associated with a higher mortality rate for the donor twin [15, 16]. When the donor twin survives after FLP, the selective FLP approach has been shown to improve catch-up growth in the smaller twin [17, 18]. Selective reduction by cord occlusion (CO) as the primary approach seems like a reasonable alternative in some cases by parents’ choice. The reported perinatal survival rate is 82–87.5% with a median GA at delivery >37 weeks [19, 20].

The wide range of complications in MC pregnancies, including TTTS, and related subgroups, such as TTTS combined with TAPS or sFGR, makes each TTTS case unique and complicated. Choosing the appropriate intervention can be challenging and may need to be individualized based on patient preferences, GA, technical difficulties, and the surgeon’s experience.

Due to the small number of TTTS cases, it is essential to centralize interventions to improve perinatal outcomes, provide high-quality care for patients, and ensure adequate training for future fetal therapy surgeons [21]. According to Robyr et al. [22] at least 20 cases per year are required to achieve expertise in the field. Due to the rarity and complexity of TTTS cases international collaboration and treatment centers of a specific size are required to enhance perinatal outcomes [23].

The Nordic countries have established the Nordic Network of Fetal Medicine (NNFM) to meet the growing need for expertise and training in fetal medicine (www.nnfm.org). The network comprises experts from the eight Nordic and Baltic countries, including Denmark, Finland, Iceland, Norway, Sweden, Estonia, Latvia, and Lithuania (Fig. 1). The collaboration began in 2014 and aims to strengthen member countries’ educational, clinical, and research activities [24]. Annual meetings, audits, and workshops allow specialists to exchange knowledge and share experiences. As part of this collaboration, the Nordic Fetal Therapy Alliance (https://www.nnfm.org/nordfetal/) was created to centralize cases requiring fetal therapy and offer treatment to patients within the Nordic region. The Nordic countries share numerous cultural and structural similarities, particularly in their robust public health systems and common language comprehension. Although parents’ perspectives toward reproductive choices may differ, legislation in Nordic countries permits pregnancy termination or selective feticide upon request until 22–24 weeks of GA, provided there is a significant risk of fetal or child disease or if pregnancy poses a maternal risk [25].

Fetal surgery is offered in three fetal medicine centers: Rigshospitalet, Copenhagen; Karolinska University Hospital, Stockholm; and Helsinki University Hospital, Helsinki (Fig. 1). All three centers have more than 20 years of experience in doing FLP, and the number of surgeons (all Maternal Fetal Medicine Specialists) during the study period was three in Copenhagen and Helsinki, and four in Stockholm. Since spring 2019, all cases of TTTS from Norway have been referred to the centers in Denmark or Sweden for evaluation and treatment. Standard common guidelines and protocols for presurgery evaluation, treatment and follow-up have been developed to ensure aligned high-quality presurgery counseling and consistent follow-up when patients return to their referring center after surgery. All fetal surgeons have obtained licenses to practice in each other countries making it possible to do exchange visits and even to perform surgery in one of the other centers if needed in special cases. This collaboration allows for greater mobility of fetal surgeons and patients within the Nordic countries, providing the best treatment options for patients while supporting the rapidly evolving fetal therapy specialty. To our knowledge, this collaboration is the first of its kind, treating all patients in the Nordic countries as one virtual center without borders. This study aims to evaluate the results of all cases of TTTS treated in the Nordic countries after establishing the Nordic Fetal Therapy Alliance and to compare them with other established international centers with published surgery outcomes.

This prospective observational cohort study involved multiple pregnancies in Sweden, Norway, Denmark, and Finland, with a GA between 15+0 and 29+0 weeks, complicated by TTTS at any Quintero stage (I-IV) between May 2019 and April 2022. All surgeries were performed at one of the national fetal therapy centers in Copenhagen, Helsinki, and Stockholm after the Nordic Fetal Therapy Alliance was established.

Exclusion criteria were TTTS stage I without an indication for intervention (long cervix and no maternal discomfort), sFGR without TTTS, and spontaneous TAPS-only cases. Patients in labor or with a dilated cervix were excluded from fetal intervention, but a short cervix (<15 mm) without contractions was not an exclusion criterion.

All patients were examined by an MFM specialist before surgery and staged strictly according to Quintero [6, 7]. Only persistent absent or reversed umbilical artery Doppler or reversed DV a-wave were classified as stage III. Patients were counselled about the benefits and risks of all treatment options including FLP, selective feticide, conservative treatment with amnion drainage or termination of pregnancy according to appropriate legislation, GA, technical issues, coexisting anomalies, or short cervix. Applying a cerclage was discussed as an option in cases with a cervix <15 mm.

Primary selective feticide was chosen as the primary treatment on parents request following counseling, if GA were below the legal limit and permission was given by application when needed by legislation. Additionally, CO was discussed with patients prior to FLP as a secondary treatment option if complete FLP was complicated or impossible.

All FLP were done using Karl Storz endoscope straight or curved, with operating sheath, depending on surgeons’ choice, most often 10 French (3 mm), but 8 French (1.3 mm) in very early cases. The FLP technique by SLPCV, its modified version, sequential selective laser coagulation or Solomon was chosen by the surgeon in each individual case. Post-surgery follow-up was done at a Fetal Medicine Center following a protocol agreed upon by the Nordic Fetal Therapy Alliance (online suppl. Materials; for all online suppl. material, see https://doi.org/10.1159/000546127).

The study’s primary outcome was perinatal survival up to 28 days after delivery. Secondary outcomes were GA at delivery, premature rupture of membranes (PPROM), post-laser TAPS, and mode of delivery. GA at delivery and mode of delivery were reported only in cases with at least one survivor. PPROM was divided into intervals before GA 28+0 weeks and between GA 28+0 and 37+0. Coexisting sFGR was defined as an estimated fetal weight discordance of more than 20% [26], and TAPS (preexisting and post-laser) was defined as peak systolic velocity in the recipient’s middle cerebral artery (MCA-PSV) being lower than 1 MoM and higher than 1.5 MoM in the donor [27]. Post-laser TAPS was evaluated at least 1 week after FLP.

All three operating centers have their own database on surgeries performed. For the purpose of this publication study, data have been shared anonymously with permission from the national data protection authorities. Written informed consent was obtained from participants to participate in the study. Consent was obtained in the country performing the surgery (Sweden, Denmark, or Finland). All necessary ethical and data protection permissions for this publication were granted by the Health Authorities and National Ethics Committees as needed in the respective countries. Sweden: National Ethics Committee, approved with ID nr: 2023-01240. Finland: regional research committee of the medical faculty of Helsinki University. HUS-yhtymä Naisten, lasten ja nuorten palvelut ID number: 7.2.2024 HUS/538/2024. Denmark data protection application ID number: VD-2019-174. Ethical approval is not required for this study in Denmark and Finland in accordance with local or national guidelines.

A total of 200 cases of TTTS were treated between May 1, 2019, and April 30, 2022, within the Nord Fetal Therapy Alliance. There were 80 cases from Sweden, 58 from Denmark, 16 from Finland, and 46 from Norway. Of the Norwegian cases, 24 had surgery in Stockholm, and 22 were treated in Copenhagen according to the collaboration agreement. Moreover, of the 200 cases, 191 involved MC diamniotic twins, while nine involved MC or dichorionic triamniotic triplets. The diagnosis, type of surgery, and GA at the surgery for all treated cases are displayed in Table 1. Four cases initially referred as TTTS turned out to be spontaneous TAPS only and were not included in this study population.

Among the total cases, 162 (81%) were solely affected by TTTS, 4 (2%) by TTTS + TAPS and 34 (17%) by TTTS + sFGR. Twenty cases (10%) underwent surgery for TTTS Quintero stage 1. All stage 1 cases had a cervix less than 25 mm or severe maternal discomfort caused by polyhydramnios.

One hundred eighty-five patients (92.5%) opted for FLP, while 15 (7.5%) chose CO as primary treatment. The median GA at surgery was 20+1 weeks with a range of 15+1 to 29+0 weeks, and 23% of cases had surgery before GA at 18+0 weeks. Outcome data were missing in 1 case, leaving a total of n = 199 cases for outcome analysis. Flowchart of patients eligible for analysis is shown in Figure 2.

In the FLP group, 18 cases (9.7%) were classified as Quintero stage I, 104 (56.2%) stage II, 58 (31.4%) stage III and 5 (2.7%) stage IV. In the primary CO group, the diagnoses were TTTS stage I with a short cervix (n = 1), TTTS stage III (n = 3), TTTS stage IV (n = 5), TTTS + sFGR (n = 5), and one DCTA triplet pregnancy where parents opted for CO on the donor of the MC pair. Six patients opted for legal termination due to complications evident after surgery. Two cases had incomplete FLP, one case had PPROM, another developed chorioamnionitis and one was diagnosed with TAPS and intracerebral hemorrhage was detected in both twins at GA 27+6, and the last one had detection of an abnormal microarray dup16p11.2 with risk of developmental delay at the routine examination of the removed amniotic fluid after laser. All six cases are included in the survival analysis as dual losses. Cases treated with primary FLP (Table 2) had an overall perinatal survival rate of 74%. At least one neonate survived at 28 days in 86% of cases, and 64% had at least two surviving babies. The median GA at delivery was 32+2 weeks (range 24+3; 41+0) in cases with at least one survivor. Among these cases 53% were delivered by cesarean section.

The perinatal survival rate was 80% in the primary CO-treated cases. The median GA at delivery was 31+5 weeks (range 26+4; 40+4) and 7/15 (58%) delivered vaginally.

Regarding complications, the risk of PPROM in primary FLP cases was 25/184 (13.8%); among these, 14 cases experienced PPROM before GA 28 weeks. In contrast none of the 15 CO cases had PPROM. The complication Post-laser TAPS occurred in 9/184 (4.9%) of FLP cases. The majority (6/9) of these cases had only one surviving neonate and in two of these cases CO was subsequently done on the donor because of severe TAPS at an early GA. These 6 patients delivered between GA 29+2 and 37+0 weeks. Three cases with post-laser TAPS had two surviving babies – all delivered by CS between GA 28+4 weeks to 31+6 weeks.

Nine triplet pregnancies were included in the study, six dichorionic triamniotic and three monochorionic triamniotic. One patient opted for CO and eight cases had FLP. Of the FLP treated, three cases had three live babies, two had two live babies, one had one live baby, and one had none. Outcome was missing in one case. Median GA at delivery was 30+2 weeks (range 26+2; 33+5) thus 2 weeks earlier than the total FLP group.

The Nordic Fetal Therapy Alliance is a collaboration between four Nordic countries: Denmark, Norway, Finland, and Sweden. This collaboration has led to the development of standard treatment protocols to provide the same high-quality advanced fetal therapy for pregnant women in this region. We report an overall postnatal survival rate of 74% for TTTS cases treated primarily with FLP, with at least one surviving twin in 86% and at least two survivors in 64%. These results are comparable to those of other well-established international centers, reporting survival of at least one in 86–88% of cases and two survivors in 60–65%, excluding triplet pregnancies [23, 28, 29]. Selective reduction by CO was the primary treatment in 8% of cases based on patients’ choices after counseling. This creates a selection bias of complex cases with a poor prognosis being offered CO instead of FLP, which could affect results in favor of double survival. Even though standard treatment protocols and indications for surgery were agreed on within countries, counseling and patients’ preferences may differ even within this geographically small region. In Denmark, 11 out of 58 (19%) of TTTS cases opted for CO as the primary treatment. Assuming that CO was performed more frequently in cases with a short cervix, more advanced stage of TTTS, or severe coexisting sFGR, this likely contributes to the higher double survival rate after FLP in Denmark.

Short cervical length or very early gestation used by some other centers as exclusion criteria due to the risk of miscarriage or very preterm birth [23‒25], were not applied as exclusion in our centers. If treatment was considered necessary and urgent, even cases as early as GA 15+1 weeks was offered FLP. It has been observed in other studies that performing FLP before 18 weeks significantly increases the risk of PPROM and very preterm birth [30]. However, in our series, a high proportion of FLP (23%) was performed before 18 weeks with a PPROM rate of 13.6%, with only 14/184 (7.6%) being born before GA 28 weeks. In the 15 CO cases in this series no experienced PPROM. While this finding may be primarily due to small sample sizes, CO is a faster procedure with risks similar to a singleton pregnancy post-surgery. Multiple studies indicate that CO may be an alternative treatment option, increasing the chance of successfully delivering one child and achieving a high GA at delivery [19, 20].

The median GA at delivery in this series was 32+2 weeks. This is in line with published reviews of perinatal outcomes in later years [23]. Internationally, the optimal timing for delivery after FLP has not yet been determined. Some centers recommend delivery around 34 gestational weeks, and others around 35–36 weeks. However, data are scarce [31]. Perinatal morbidity is expected to be low after 32 gestational weeks [32], and elective delivery in the absence of post-surgery complications before 36 gestational weeks does not appear to reduce perinatal risks [33]. The countries of the Nordic Fetal Therapy Alliance have reached a consensus and recommend elective delivery between 36+0 and 37+0 gestational weeks in uncomplicated pregnancies after FLP. But even so, the difference in GA at delivery, as seen in Table 2 is quite different between countries.

The first 3 years of collaborating on TTTS treatment highlight that despite significant time and effort invested in establishing common protocols for presurgery, surgery, and post-surgery management, differences still exist between centers. Although legislation and protocols are very similar, patients seem to have different preferences and ethical considerations between our countries and surgeons may have different counseling strategies and opinions on optimal treatment. Even with similar equipment, experience, approaches, and techniques for treating TTTS may differ. This of course is a limitation when comparing numbers between centers and to other centers. However, the main scope of this paper is on the feasibility to work together between countries to improve the quality of patient care.

Before the establishment of The Nordic Fetal Therapy Alliance, Norway used to send complicated MC pregnancies outside of the Nordic region to other European centers for fetal intervention. However, in 2019, fetal medicine experts from Nordic countries agreed to treat patients with TTTS within this collaboration. This partnership represents one of the pioneering international fetal therapy centers. The significance of high-volume fetal therapy centers that speed up the learning curve and experience is indisputable. This partnership provides a virtual multidisciplinary team of experts capable of discussing and managing cases to improve outcomes. Additionally, the mobility of the experts between the centers offers a unique training opportunity for sharing knowledge and experience. This partnership is also beneficial to address challenges in reporting outcomes, comparing treatments, and developing management guidelines [34].

Many of the cases in this publication were treated during the COVID-19 pandemic. The pandemic has had a negative impact on the management of TTTS cases worldwide, primarily due to the limited ability to travel. This has been reported to result in more advanced stages of TTTS at diagnosis, a higher number of cases with a short cervix, and fewer cases eligible for fetal therapy, leading to poorer perinatal outcomes [35]. However, the Nordic Fetal Therapy Alliance did not encounter these difficulties, and all patients received treatment either by traveling by car to the nearest fetal center or the center with the least restrictive policies at a given time. This collaboration of four Nordic countries has led to a new era for the fetal surgery community. It has overcome the challenges of performing fetal interventions in low-volume settings. Furthermore, the advantages of this alliance include standardized treatment protocols and follow-up strategies that provide the same quality of fetal therapy to all patients. In addition, younger fetal therapists have access to different fetal therapy centers for educational, training, and research purposes.

We want to thank Fredrika Odelstierna for coordinating the Norwegian patients between centers and assisting in collecting data as well as Marius Kublickas and Sverker Ek for their surgical expertise in performing some of the fetal interventions at Karolinska University Hospital.

Written informed consent was obtained from participants to participate in the study. Consent was obtained in the country performing the surgery (Sweden, Denmark, or Finland). All necessary ethical and data protection permissions for this publication were granted by the Health Authorities and National Ethics Committees as needed in the respective countries. Sweden: National Ethics Committee, approved with ID number: 2023-01240. Finland: regional research committee of the medical faculty of Helsinki University. HUS-yhtymä Naisten, lasten ja nuorten palvelut ID number: 7.2.2024 HUS/538/2024. Denmark data protection application ID number: VD-2019-174. Ethical approval is not required for this study in Denmark and Finland in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

The establishment of Nordic Network of Fetal Medicine and Nordic Fetal Therapy Alliance was funded by a grant from The Nordic Council. The funder had no role in the design, data collection, data analysis, and reporting of this study. All patients participating in this study were treated within the normal hospital budgets.

L.N.N. and M.S.: conceptualization, investigation, methodology, data analysis, original draft writing and editing. G.M., B.K., P.L., K.S., V.S., L.H., E.T., L.S., and A.T.: conceptualization, methology, investigation, data collection validation, review, and editing.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.