Proximate Cord Insertion in Twin-to-Twin Transfusion Syndrome: Case Series and PRISMA Compliant Systematic Review and Meta-Analysis

What does this study add to current knowledge?

• This is the first study to evaluate the significance of presence of proximate cord insertions in TTTS pregnancies and investigate the clinical outcomes following various therapeutic options, specifically laser ablation in a PRISMA compliant systematic review.

What are the main clinical implications?

• The study provides important clinical information to counsel patients with TTTS pregnancies in the presence of proximate cords in regard to management approaches and potential outcomes.

Anomalies of umbilical cord insertion are more common in twin gestations compared to singletons [1]. Several studies have demonstrated an association between abnormal umbilical cord insertion and adverse pregnancy outcomes in monochorionic (MC) twin gestations [2‒4]. Most of this available literature focuses on velamentous and marginal cord insertions.

Another type of abnormal cord insertion in MC twins is proximate cord insertion (PCI) [5]. Presence of PCI poses technical challenges during fetoscopic laser surgery (FLS) of twin-to-twin transfusion syndrome (TTTS) given the chaotic distribution of vascular anastomoses resulting in difficulty in identifying the intertwin vascular equator [6‒8]. Our group has previously published a case report of modified fetoscopic surgical technique in TTTS cases with PCI [9].

The management of PCI in the setting of TTTS and resultant neonatal outcomes after the laser procedure are not well described in the literature. The hypothesis of our study is that there is no difference in clinical outcomes in TTTS cases treated with FLS with and without PCI.

This was a retrospective cohort study of prospectively collected data of consecutive TTTS cases that underwent FLS at the University of Maryland Advanced Fetal Care Center between 2012 and 2020. The study was approved by the University of Maryland at Baltimore Institutional Review Board and Ethics Committee (HP-00040715-12). Informed consents were obtained from all participants.

Patients referred to our center for evaluation of TTTS underwent comprehensive ultrasound examination, including anatomical assessment, placental and umbilical cord insertions mapping, biometry measurements, fetal echocardiography, and Doppler studies for the diagnosis and staging of TTTS based on the Quintero system [10]. Selective fetal growth restriction (sFGR) was defined according to the Delphi consensus criteria as presence of either an estimated fetal weight (EFW) <3rd centile in one twin or at least two of the following: EFW of one twin <10th centile, abdominal circumference of one twin <10th centile, EFW discordance ≥25%, or umbilical artery pulsatility index (UA PI) of the smaller twin >95th centile [11]. Ultrasound exams were performed by registered diagnostic medical sonographers supervised by experienced fetal medicine specialists.

In cases of suspected PCI, the distance between cord insertions was measured and recorded. PCI was defined as a distance equal or less than 4 cm between placental cord insertions [5].

All cases with TTTS stage II or higher were offered surgical intervention, as were stage-I cases if they presented with a short cervix of less than 25 mm or symptomatic polyhydramnios. Complete FLS procedure data including umbilical cord insertion sites were recorded during each procedure and entered in the institutional TTTS dataset afterward.

FLS was performed using a single-port fetoscope under either local anesthetic in conjunction with intravenous sedation or regional anesthesia. Direct entry technique was used in all cases. A diode laser was used to ablate all intertwin vascular anastomoses using selective or sequential selective method followed by equatorial dichorionization “Solomon technique” [12] if technically feasible. When needed, amnioinfusion was performed to improve visualization. If amniodrainage was necessary, it was performed following the coagulation phase of the procedure.

Our previously described modified FLS technique for TTTS cases with PCI briefly comprised identifying the most distal branch of the recipient’s vessel that is closest to the donor’s sac as the starting point for vascular equator mapping. Following coagulation of the meticulously identified intertwin vascular anastomosis, coagulation points were connected peripherally starting from the most distal point to the cord insertions moving inward. An area of 1–2 cm around the cord insertions was left untouched without connecting the coagulated points in both directions [9].

Following FLS, patients remained in the hospital for a minimum of 24 h. After discharge, patients were either followed by the fetal center if feasible or returned to the referring provider.

Information about pregnancy outcomes was collected prospectively either from our institution medical records or from the referring physicians as a part of follow-up care. The collected perinatal data included maternal demographics, preoperative, operative, postoperative, and neonatal outcomes, as outlined in the tables in the Results section.

Continuous variables were reported using median (interquartile range [IQR]). Categorical and binary variables were reported using count (percentage). The Wilcoxon rank-sum test was used to compare continuous variables between the groups, and Fisher’s exact test was used to compare continuous and binary variables. Two controls were randomly selected by the statistical software. Each case and control perfectly matched for preoperative variables including Quintero stage, sFGR (yes/no), anterior placenta (yes/no), preoperative cervical length (<25 mm/≥25 mm), and gestational age (GA) at fetal intervention (<18 weeks/≥18 weeks) [13‒20]. All statistical analyses and random selection of the controls were performed using the Stata 16 software.

The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [21]. PubMed, Scopus, CINAHL, and Medline databases were searched from inception until January 2021. The search terms representing the participants (twin) were combined with association terms (cord or insertion). Studies reporting on PCIs in MC pregnancies complicated with TTTS were included in order to construct a review table. Narrative review articles, systematic reviews, and conference abstracts were excluded. All the extracted studies were transferred into Covidence, an automated web application designed to screen the papers for systematic reviews. After removing the duplicates, 85 records were included for title/abstract screening by two independent reviewers (H.M., H.T.), and the third reviewer evaluated the conflicting results (O.T.) (Fig. 1). The following variables were extracted from the full text of included records: year of publication, country of the study, case numbers, TTTS Quintero staging, GA at the FLS, GA at delivery, procedure to delivery interval, overall fetal survival, and overall neonatal survival rate. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies and risk of bias. NOS comprises “participant selection,” “comparability of study groups,” and “assessment of outcome or exposure.” A score above 7 is considered as high quality [22].

A total of 262 consecutive FLS for TTTS were performed in our fetal center at the University of Maryland, Baltimore, during the study period. We excluded 16 TTTS cases that were triplet pregnancies. Of the remaining 246 pregnancies, a total of 5 cases (prevalence of 2%) had PCIs. All of the 5 cases with proximate cords were identified on the pre-laser ultrasound exams and confirmed afterward under direct visualization during fetoscopy. Placental histopathological exams were not available, given that all cases delivered at their referring institutions. Ultrasound images showing the proximate cords for the 5 cases can be seen in Figure 2. No TTTS cases with PCI were treated with other interventions such as cord coagulation during the study period. Baseline characteristics of TTTS cases with proximate cords with unmatched cohort and matched controls are summarized in Table 1.

There were no significant differences in preoperative factors. All 5 cases of proximate cords were stage III and had donor sFGR, of which three had absent or reversed UA velocity Dopplers. GA at fetal intervention was performed at later GA in proximate cord cases with median of 24.2 weeks versus 20.3 weeks in the nonproximate cord group. Findings were similar following matching (Table 2).

Complete equatorial dichorionization was not performed in all five proximate cord cases as a result of our modified procedure technique (explained in the Materials and Methods section). Procedure time was significantly longer (median of 61.4 min in proximate cord vs. 37.5 min in nonproximate cord, p < 0.001), and amnioinfusion was significantly more common (100% in proximate cord vs. 43% in nonproximate cord, p = 0.01). There were no significant differences in the cannula size, visibility, presence of AA or VV anastomoses, and occurrence of septostomy between groups (Table 3). Findings were similar following matching.

Pregnancies in the nonproximate cord group delivered at later GA with median of 32.6 weeks (IQR: 29.2, 34.5) versus 28.6 weeks (IQR: 28.3, 30.6) in the proximate cord cases and had longer FLS-to-delivery interval (median of 81.2 days in the nonproximate cord vs. 35 days in the proximate cord), although these differences were not statistically significant. There were no significant differences in live births and neonatal survival. There were no recurrent TTTS, twin anemia polycythemia sequence (TAPS), or relaser in both groups. There were no significant differences in neonatal outcomes (Table 4). Findings were similar following matching.

Search yielded 244 articles. After excluding the studies by reviewing the abstracts, 4 studies reporting on the clinical outcomes of PCIs in TTTS were retrieved. Table 5 shows studies’ characteristics. Studies were all in the form of case reports and series. There are a total of 19 cases reported, including 5 cases from the present study. Sixteen out of the 19 cases presented at or beyond stage-III TTTS. Of those 19 cases, 13 were managed by FLS, 3 by amnioreduction, and 3 by selective reduction. FLS was deemed technically not feasible in a single case, for which amnioreduction alone was performed [8].

In the FLS group (n = 13), 3 pregnancies encountered fetal demise, of which one was dual demise on postoperative day 5, and the other two fetal demises were both type-II sFGR with persistently abnormal Dopplers starting before the laser procedure. There was one post-laser TAPS. GA at delivery ranged between 27 and 37 weeks in this group. All surviving fetuses survived beyond the neonatal period.

In the amnioreduction group (n = 3), there were no fetal demises. The 3 cases delivered at 24, 33.5, and 35.7 weeks. In the case that delivered at 24 weeks, both newborns did not survive the neonatal period. The other 2 cases had dual neonatal survival. In the selective reduction group (n = 3), GA at delivery ranged between 34 and 36 weeks, and all the remaining fetuses survived the neonatal period.

Table 6 shows the pooled proportions of occurrence of outcomes in proximate cord cases managed by FLS only. Preterm birth rate less than 28 weeks and less than 32 weeks was 28% and 74%, respectively. The overall fetal survival and neonatal survival was 85% and 80%, respectively.

The main findings of our study are prevalence of TTTS with proximate cords noted to be 2% (5/246) similar to what reported by others [6, 7]. All the cases were managed by FLS at our center. Procedure time was significantly longer and use of amnioinfusion was more common in the proximate cord cases compared to the nonproximate cord controls. Only 1 case encountered fetal demise of which the fetus had sFGR with persistently abnormal UA Dopp­lers starting prior to the laser procedure that continued afterward. Although not statistically significant, median GA at delivery in the proximate cord group was almost 3 weeks earlier than the nonproximate cord group. All the remaining fetuses survived beyond the neonatal period.

Systematic review yielded total of 19 cases of proximate cords with TTTS. Cases were managed by various options, including FLS, amnioreduction, and selective reduction which resulted in mixed inconsistent clinical outcomes. FLS was deemed not feasible in single case for which amnioreduction alone was performed. Out of the 13 cases that were managed by FLS, preterm birth rate less than 28 weeks and less than 32 weeks was 28% and 74%, respectively. The overall fetal survival and neonatal survival was 85% and 80%, respectively. Residual anastomoses were common following FLS procedures [6].

Angiovascular architecture in MC placentas with proximate cords is random and chaotic resulting in serious technical challenges during the laser procedure which could either preclude the procedure completely or result in incomplete laser surgery. Post-laser residual anastomoses are common as dye studies showed in one of the included series [6]. Same series had 1 case of post-laser TAPS. In our series, no post-laser TAPS was encountered. Although it is not ideal to draw conclusions due to small sample size and absence of dye studies in our series, but performing our previously described modified fetoscopic technique [9] in which the coagulation points were connected peripherally leaving out an area of 1–2 cm around the cord insertions could have resulted in no residual vascular anastomoses of small diameter which are known to frequently result in post-laser TAPS [23, 24]. The area around the proximate cords is usually a habitant of larger anastomosis and specifically AA anastomoses (AAA) of more than 3 mm in diameter that connects both cords while smaller diameter vessels tend to be in the periphery [25, 26]. Although coagulating all connecting vessels is ideal, but the size of these AAA and their proximity to placental cord insertions may render them difficult or impossible to coagulate. In the series described by Gandhi et al. [7] (6 cases), only 1 case underwent laser which was complicated with dual twin demise 5 days post-laser. Placental examination showed large residual AAA connecting both cords which was thought had resulted in the demise. Based on that outcome, that group decided not to proceed with laser in future cases with proximate cords for which the following 5 cases were managed by either amnioreduction or selective reduction. AAA are known to prevent the development of TTTS in MC pregnancies [27]. Similarly, monoamniotic placentas are characterized with PCIs and a high prevalence of AAA. Concomitantly, monoamniotic twin pregnancies have also a reduced risk of developing TTTS due to the presence of those anastomoses [28, 29]. However, due to hemodynamic changes, protective bidirectional AAA can change to behave as disease causing functional unidirectional AV anastomoses [30] which could explain the dual demise in their series. Once case reported the use of endoclip for the AAA very close to the cord insertion [31].

Different definitions of proximate cords were used in the literature, ranging from side-to-side cords to less than 5-cm distance between the cords. Zhao et al. [5] analyzed a total of 369 MC placentas and established reference ranges for the distance between cord insertions across GAs in MC placentas. They defined proximate cords as the distance of less than 5th percentile which was equal or less than 4 cm. Similar definition was used in our series.

In the present study, we did not observe any differences in clinical outcomes following FLS in TTTS cases with proximate cords compared to nonproximate cord controls even after matching for preoperative covariates. Similarly, no differences in clinical outcomes were demonstrated by Zhao et al. [6] in complicated MC pregnancies with proximate cords and by Hack et al. [28, 32] in uncomplicated monoamniotic and MC pregnancies with proximate cords.

Based on these outcomes, we recommend against abandoning fetoscopic surgery completely in TTTS cases with proximate cords as was recommended by Gandhi et al. [7]. Fetoscopic surgery can be both diagnostic and therapeutic. If laser surgery deemed not feasible by fetoscopy, amnioreduction or selective reduction appear to be reasonable alternative options and should be discussed with parents prior to proceeding with fetoscopy. Fetoscopic laser procedures in the presence of proximate cords are technically challenging, even for well-trained highly experienced surgeons, and require longer time to identify the vascular anastomoses. Inspection of the vascular equator may be impossible if part of the intertwin anastomoses are located in the other twin’s sac. In this situation, management should be individualized to either amnioreduction alone, or combined with intentional septostomy [33], or through a second entry in the other twin’s sac [34].

We acknowledge our limitations and the data should be interpreted with care due to the retrospective nature of the study and the small number of cases with PCIs, limiting the ability to make strong inferences. The study was performed on a population of referred patients who underwent FLS which might under- or overestimate the prevalence of proximate cords with TTTS. We were not able to review placental pathologic findings because most of our cases involved referrals from other institutions.

In conclusion, although detailed preoperative sonographic mapping of the placenta and placental umbilical cord insertions in all TTTS cases is empirically invaluable for proper operative planning, the feasibility of FLS in TTTS cases with proximate cords can only be determined by fetoscopy. Amnioreduction and selective reduction should be discussed as alternative options if the FLS procedure deemed to be technically not feasible. It is imperative to emphasize that the small number of cases make it impossible to draw positive or negative conclusions. Future prospective studies are required to determine the best treatment in TTTS cases with PCIs.

Authors would like to thank all the staff and workers of the fetal care center at the University of Maryland for their hard work and dedication to deliver the best care for our patients.

Subjects have given their written informed consent and the study protocol was approved by the University of Maryland committee on human research (HP-00040715-12).

The authors have no conflicts of interest to declare.

Study was funded by the University of Maryland internal departmental funds.

H.J.M. and O.M.T. conceived the study and designed the protocol. H.J.M. and H.T. collected the data. H.J.M. wrote the first draft of the paper. O.M.T. and H.T. were involved in the statistical analysis and drafting the results. N.P. and C.H. were all involved in critical analysis of the data. All authors contributed significantly to critical revisions of successive drafts of the manuscript. H.J.M. and O.M.T. are the guarantors of the review.

Data are available upon request from corresponding author.