Therapy For Twin-twin Transfusion Syndrome Research Articles

The Arabin cervical pessary for the prevention of preterm birth in twin-to-twin transfusion syndrome treated by fetoscopic laser coagulation: a multicenter randomized controlled trial

BackgroundMiscarriage and preterm birth are leading causes of loss and disability in monochorionic twins following laser treatment for twin-twin transfusion syndrome. ObjectiveWe investigated the use of the cervical pessary to reduce preterm birth before 32 weeks in monochorionic diamniotic twin pregnancies after fetal surgery for twin-twin transfusion syndrome. Study designIn this open-label multicenter randomized trial pregnant women carrying monochorionic diamniotic twins requiring fetoscopic laser coagulation for twin-twin transfusion syndrome were randomly assigned in a 1:1 ratio to pessary placement or conservative management. The primary outcome was birth before 32 weeks. Secondary outcomes were birth before 28, 30, 34 or 37 weeks, preterm rupture of membranes, fetal and neonatal survival, and a composite of maternal and neonatal complications. The estimated sample size was 364 patients, with 182 cases in each arm of the study. The analysis was performed according to the intention-to-treat principle. Two interim analyses were planned. ResultsThe trial was stopped prematurely after the first planned interim analysis for futility. One hundred thirty-seven women were included in the analysis, 67 in the pessary and 70 in the conservative management group. A preterm birth before 32 weeks occurred in 27/67 women (40.3%) in the pessary group and in 25/70 women (35.7%) in the conservative management group (aOR, 1.19; 95%CI, 0.58-2.47, P=.63). No significant differences between groups were observed in the rate of deliveries before 28, 30, 34 and 37 weeks, respectively. Overall survival to delivery was 91.2% (125/137) for at least one twin and 70.8% (97/137) for both twins, with no differences between groups. Neonatal survival at 30 days was 76.5% (208/272). There were no differences between groups in maternal or neonatal morbidity. ConclusionIn monochorionic diamniotic twin pregnancies requiring fetal therapy for twin-twin transfusion syndrome, routine use of cervical pessary did not reduce the rate of preterm delivery before 32 weeks.

Two Year Neurodevelopmental Outcome after Fetoscopic Laser Therapy for Twin-Twin Transfusion Syndrome: Comparison with Uncomplicated Monochorionic Diamniotic Twins.

Twin-twin Transfusion Syndrome (TTTS) represents a significant complication in monochorionic twin pregnancies, caused by an unbalanced shunting of blood through intertwin placental vascular anastomoses. Despite advances in fetoscopic laser surgery, TTTS is still associated with a high rate of cerebral injury. However, there are no studies comparing these pregnancies with uncomplicated monochorionic diamniotic (MCDA) twin pregnancies, establishing the baseline risk of neurodevelopmental impairment. The aim of this study is to evaluate the odds of neurodevelopmental impairment in MCDA twins who undergo fetoscopic laser surgery for twin-twin transfusion syndrome, in comparison to a cohort of uncomplicated MCDA twin pregnancies. This is a retrospective cohort study of children born from MCDA twin pregnancies at a single center between 2008 and 2019. A routine, standardized follow-up assessment was conducted at a minimum of 2 years after delivery. The primary outcome of this was a 2 year neurodevelopmental impairment. Neurological, motor, and cognitive development was assessed by using the revised Brunet-Lézine scale. 176 children met the enrolment criteria. Of these, 42 (24%; TTTS group) underwent fetoscopic laser surgery for TTTS during pregnancy, and 134 (76%; uncomplicated MCDA group) were uncomplicated MCDA pregnancies. The primary outcome was found in four children (9.52%) in the TTTS group and ten children (7.46%) in the uncomplicated MCDA group (p = 0.67, aOR 2.82, 95% CI 0.49-16.23). Major neurologic impairment was found in 2.38% after fetoscopic laser surgery and 1.49% in uncomplicated MCDA twins (p = 0.70, aOR 0.97, 95% CI 0.22-4.24). The data were adjusted by birth order, birth weight, and gestational age at birth. The outcome in MCDA twins who underwent fetoscopic laser surgery for TTTS is comparable to the outcome in uncomplicated MCDA twins. Our findings emphasize the need for long-term neurodevelopmental follow-ups in all children from monochorionic twin gestations.

Highlights from the International Twins Congress 2021

Highlights from the International Twins Congress 2021

Current Status of the Workforce and Training at Fetal Therapy Centers in North America

Introduction: We sought to characterize the current workforce and training for fetal intervention procedures at fetal centers in North America. Methods: An anonymous electronic survey was developed to query the 34 centers in the North American Fetal Treatment Network regarding the demographics and training of their faculty. Telephone surveys were conducted with directors of known fetal intervention fellowships. Results: More than 50% of maternal-fetal medicine (MFM) faculty at fetal centers were female; more than two-thirds of pediatric surgical faculty were male. Most of the training of faculty was undertaken by visiting more experienced centers or having new faculty work with more experienced ones at the same center. Current fetal intervention fellowships appear to achieve levels of competency for intrauterine transfusions and laser therapy for twin-twin transfusion syndrome. Two-thirds of centers stated that they would be able to offer a position to an MFM who completed a formal fellowship in fetal intervention. Conclusion: A collaborative effort should be undertaken to establish formal fellowships in fetal medicine and intervention.

Impact of Obesity on Pregnancies Undergoing Laser Therapy for Twin-Twin Transfusion Syndrome

Introduction: We sought to determine if maternal obesity, defined by body mass index (BMI) 30–34.9 or BMI ≥35, negatively impacts the technical aspects and pregnancy outcomes in women treated with selective laser photocoagulation of placental communicating vessels for twin-twin transfusion syndrome (TTTS). Methods: Retrospective review of women undergoing laser for TTTS from January 2010 to December 2021. Outcomes were stratified based on maternal BMI <30, 30–34.9, and ≥35. Data obtained included maternal age, parity, ethnicity, gestational age at laser, placental location, Quintero stage, CHOP cardiovascular score, operative and anesthesia times, procedure-to-delivery interval, gestational age at delivery, survival to birth, survival to discharge, and the presence of residual anastomoses. Statistical analysis included the χ² or Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables with p < 0.05 being significant. Results: A total of 434 women underwent laser for TTTS during the study period. Of those, 274 (63%) had a BMI of <30, 92 (21.2%) had a BMI between 30 and 34.9, and 68 (15.7%) had a BMI ≥ 35. There were no differences in maternal age, parity or ethnicity, Quintero stage, CHOP cardiovascular score, placental location, operative time, laser-to-delivery interval, gestational age at delivery, survival outcomes, or the presence of residual anastomoses between the three groups. Patients with a BMI of 30–34.9 were operated on at a slightly later gestational age, and those with a BMI > 35 had longer operative and anesthesia times. There were no technical failures as a result of BMI ≥ 30 or 35. Conclusion: Using appropriate technical adjustments, outcomes for obese women undergoing laser for TTTS are similar to nonobese women, although patients with BMI ≥35 have longer operative and anesthesia times.

Maternal-Fetal Medicine: The Journey Thus Far and Way Forward

Maternal-Fetal Medicine: The Journey Thus Far and Way Forward

857 Long-term outcomes in children treated with laser therapy for twin-twin transfusion syndrome

In the U.S., patients who undergo fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS) may travel great distances for care. Many cannot return to study sites for evaluation due to geographic location. We used internet-based Ages and Stages Questionnaire (ASQ-3) surveys to collect parent-reported outcomes in children treated for TTTS. Survey of patients residing in 23 different U.S. states who underwent FLP for TTTS or TAPS at a single center from 2013 until 2019. Patients with ≥ 1 neonatal survivor were invited to complete the ASQ online if their child was between 2-60 months corrected age. Repeat survey was performed after 12 months. ASQ scores indicating typical development or improvement after 1 year were classified “Favorable”. Scores indicating atypical development or decline were classified “Unfavorable”. Comparative statistics were performed including stratified analysis of results by ASQ domains. 276 mothers met inclusion criteria, of which the ASQ was completed by 81 patients. After 12 months, 61 patients were eligible for repeat ASQ, of which 31 responded (follow-up rate of 51%, total 58 repeat child assessments). Median pediatric age of responders at initial assessment was 20.0 (IQR, 8.5 – 39.0) months. Among non-responders, children were older at follow-up (p <0.001) and more likely to be from the Southern U.S. (p=0.002).(Table 1) Among children who repeated the ASQ, early gestational age and the loss of a co-twin was associated with “Unfavorable” composite scores. Similar findings occurred at the individual domain level assessment of Gross Motor, Problem Solving and Personal-Social skills.(Table 2) This is the first successful attempt to use internet-based technology to assess long-term pediatric outcomes via the ASQ-3 in a U.S. cohort of children treated with FLP for TTTS. Prematurity and co-twin demise appear to be the greatest risk factors for abnormal childhood development.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Evaluation of cardiac function in the recipient twin in successfully treated twin-to-twin transfusion syndrome using a novel fetal speckle-tracking analysis.

This study was designed to evaluate ventricular size, shape, and function in recipient twins following laser therapy for twin-twin transfusion syndrome (TTTS), using novel speckle-tracking techniques. This retrospective study enrolled patients that underwent fetal laser surgery for TTTS and had fetal echocardiograms (FE) performed pre- and post-operatively (op), with adequate resolution in the 4-chamber view for analysis, using a speckle-tracking software, to compute the size, shape, and function of both the right (RV) and left (LV) ventricles. Values were indexed to published normal values. Pre- and post-laser Z-score values for each of the measurements were compared using the Student's t-test, with significance defined as P < 0.05. Fifteen TTTS candidate pregnancies that underwent laser therapy between 2010 and 2017, with adequate pre- and post-op FE, were selected for the analysis. Post-op FE at 28.5 ± 8.3 days showed a significant decrease in RV base dimension, increased LV base dimension, and improvements in many functional measurements: LV global and free wall strain, LV fractional area change, LV basal-apical fractional change, and LV and RV 24-segment fractional shortening (FS) of the basal segments. Cardiac remodeling, following laser surgery in TTTS recipient twins, was demonstrated in the basal portion of both the RV and LV with improved biventricular function.

North American Fetal Therapy Network: timing of and indications for delivery following laser ablation for twin-twin transfusion syndrome

Despite improvements in fetal survival for pregnancies affected by twin-twin transfusion syndrome since the introduction of laser photocoagulation, prematurity remains a major source of neonatal morbidity and mortality. To investigate the indications and factors influencing the timing of delivery following laser treatment, we collected delivery information regarding twin-twin transfusion syndrome cases in a large multicenter cohort. Eleven North American Fetal Therapy Network (NAFTNet) centers conducted a retrospective review of twin-twin transfusion syndrome patients who underwent laser photocoagulation. Clinical, demographic and ultrasound variables including twin-twin transfusion syndrome stage, and gestational age at treatment and delivery were recorded. Primary and secondary maternal and fetal indications for delivery were identified. Univariate analysis was used to select candidate variables with significant correlation with latency and GA at delivery. Multivariable Cox regression with competing risk analysis was utilized to determine the independent associations. A total of 847 pregnancies were analyzed. After laser, the average latency to delivery was 10.11 ± 4.8 weeks and the mean gestational age at delivery was 30.7 ± 4.5 weeks. Primary maternal indications for delivery comprised 79% of cases. The leading indications included spontaneous labor (46.8%), premature rupture of membranes (17.1%), and placental abruption (8.4%). Primary fetal indications accounted for 21% of cases and the most frequent indications included donor non-reassuring status (20.5%), abnormal donor Dopplers (15.1%), and donor growth restriction (14.5%). The most common secondary indications for delivery were premature rupture of membranes, spontaneous labor and donor growth restriction. Multivariate modeling found gestational age at diagnosis, stage, history of prior amnioreduction, cerclage, interwin membrane disruption, procedure complications and chorioamniotic membrane separation as predictors for both gestational age at delivery and latency. Premature delivery after laser therapy for twin-twin transfusion syndrome is primarily due to spontaneous labor, preterm premature rupture of membranes and non-reassuring status of the donor fetus. Placental abruption was found to be a frequent complication resulting in early delivery. Future research should be directed toward the goal of prolonging gestation after laser photocoagulation to further reduce morbidity and mortality associated with twin-twin transfusion syndrome.

Subsequent fertility, pregnancy, and gynecologic outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome compared with normal monochorionic twin gestations

An improved survival and quality of life for neonatal survivors after fetoscopic laser therapy for twin-twin transfusion syndrome has been reported. However, little is known about the medium-term maternal effects after fetoscopic laser therapy with respect to reproductive and gynecologic outcomes. The objective of this study was to document reproductive, obstetric, gynecological, and psychological outcomes in women who underwent fetoscopic laser therapy for twin-twin transfusion syndrome. This was a monocentric controlled study on consecutive women who underwent fetoscopic laser therapy for twin-twin transfusion syndrome between 2007 and 2013 at the University Hospitals Leuven (cases; n= 198). Controls were women followed up during the same time period for an uncomplicated monochorionic diamniotic twin pregnancy and with an uneventful course (controls; n= 211). All patients received a questionnaire inquiring on their fertility, later pregnancies, and gynecological outcomes. The response rate was 50.4% (cases: n= 95; controls: n=109). Most baseline characteristics were similar across both groups. Women in the fetoscopic laser therapy group attempted a new pregnancy more frequently (34% [31 of 92] vs 21% [22 of 107] in controls; P < .05) and became pregnant more often (100% [31 of 31] vs 82% [18 of 22]; P<.05).We observed a shorter interpregnancy interval in cases than controls (median interval, 12 [interquartile range, 5-27] vs 24 [interquartile range, 15-30] months) (P < .05). This was also observed in cases who lost one or both fetuses or babies in the index pregnancy (median interval, 9 [interquartile range, 3.5-25.5] months; P < .05). The complication rate during subsequent pregnancies (26% [8 of 31] vs 11% [2 of 19]; P=.194) and at delivery (17% [5 of 30] vs 11% [2 of 19]; P= .554) were comparable. More women who underwent fetoscopic laser coagulation reported relevant psychological symptoms (44% [40 of 92] vs 21% [23 of 107]; P < .05). When only women in whom there was a double-surviving twin pair were considered, there were no differences in psychological symptoms compared with controls (16% [15 of 55] vs 21% [23 of 107]; P= .411). Gynecological problems were equally frequent in both groups (20% [18 of 92] vs 31% [33 of 107]; P= .069). No adverse medium-term maternal effects with respect to fertility, obstetric, and gynecological outcomes were observed after fetoscopic laser therapy. However, these women reported more psychological or emotional problems than women with monochorionic diamniotic who did not have laser therapy, in particular when this was complicated by a fetal loss.

Incidence of and Risk Factors for Residual Anastomoses in Twin-Twin Transfusion Syndrome Treated with Laser Surgery: A 15-Year Single-Center Experience

Objectives: To evaluate the incidence of residual anastomoses (RA) after laser therapy for twin-twin transfusion syndrome (TTS) and investigate risk factors for incomplete laser surgery. Material and Methods: All available TTS placentas treated with laser at our center between 2002 and 2016 were injected with color dye to assess the presence of RA. We evaluated the incidence of RA over the past 15 years by dividing the cohort into three time periods, and studied the association with risk factors and neonatal outcome. Results: Overall, RA were detected in 21.0% (78/371) of placentas. The incidence of RA decreased from 38.8% (26/67) in the initial period to 11.7% (16/137) in the most recent period (p < 0.001). On multivariate analysis, several risk factors were independently associated with the risk of RA, including Solomon laser technique (odds ratio [OR] 0.17, 95% CI 0.09–0.33) and estimation of surgical success (OR 19.28, 95% CI 8.17–45.49). Premature delivery and neonatal morbidity occurred more often in TTS cases with RA. Conclusions: The incidence of RA after laser therapy for TTS decreased significantly in the past 15 years and is now below 15% due to the use of the Solomon technique.

Risk of donor demise after laser therapy for twin–twin transfusion when complicated by growth discordance and abnormal umbilical artery Doppler findings*

Objective: To investigate the natural course of abnormal umbilical artery Doppler (UAD) findings in donor fetuses after laser surgery and the prognostic significance of resolution, persistence, or new onset UAD abnormalities with and without the presence of preoperative growth discordance.Study design: Retrospective cohort study of all monochorionic-diamniotic multi-fetal gestations diagnosed with twin-twin transfusion syndrome (TTTS) undergoing laser surgery at a single large metropolitan referral center from 2010-2016. The estimated fetal weight was measured preoperatively and the UAD were measured both pre- and postoperatively (median = 8 days). Patients were grouped according to the presence of abnormal UAD with or without growth discordance pre- and postoperatively. Risk ratios (RR) were calculated for each group for risk of intrauterine fetal demise compared to the pre- and postoperative normal UAD groups as the referents.Results: There were eighty-one women who met inclusion criteria throughout the study period. Forty-three (53.1%) patients had abnormal donor twin UAD preoperatively and 33 (40.7%) were diagnosed with growth discordance. However, 13 (44.8%) had normalization of the UAD postoperatively (median = 8 days) with a similar rate of donor fetal demise as the non-discordant preoperative normal UAD group (7.7% versus 10.3%, p = .79). Abnormal preoperative UAD was associated with an increased risk of donor demise (RR 3.6, CI 1.1–12.1), which was further elevated in the presence of growth discordance (RR 5.2, CI 1.7–16.3). The greatest risk for donor demise was seen if the UAD remained abnormal postoperatively with concomitant growth discordance (RR 10.3, CI 2.5–41.6). Conclusions: Preoperative abnormal donor UAD is a significant risk for donor demise post-laser therapy for TTTS. Persistent postoperative abnormal UAD with concomitant growth discordance confers the greatest risk for donor demise. However, resolution of abnormal UAD has a similar rate of donor demise when compared to patients with normal UAD preoperatively.

Estimated combined cardiac output and laser therapy for twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) is the major cause for fetal demise in monochorionic diamniotic pregnancies. Estimated combined cardiac output (CCO) has not been studied in this setting. The primary aims of this study were to compare CCO in twin donor and recipient fetuses and assess differences in CCO before and after laser coagulation therapy. A secondary aim was to evaluate the relationship of CCO with perinatal mortality, defined as intrauterine or neonatal mortality (≤30days of age) in fetuses that underwent laser coagulation therapy. We performed a retrospective review of fetuses with TTTS who received echocardiograms prior to laser therapy. Prelaser echocardiograms were performed in 66 fetuses, of which 45 (21 donor and 24 recipient) survived to the postlaser echocardiogram. Donor CCO increased from a mean of 487±137mL/min/kg prelaser to 592±128mL/min/kg postlaser (P=.025). There was no significant change in mean recipient CCO from prelaser 551±165mL/min/kg to postlaser 575±112mL/min/kg (P=.564). In recipient fetuses, higher prelaser CCO correlated with increasing Quintero stage (P=.010) and perinatal mortality (P=.003). Thirty-day postnatal outcome data were available for 38 fetuses, of whom 34 (89%) survived. Amongst survivors, 25 (74%) experienced an increase in CCO, while 9 (26%) experienced a decrease in CCO (P=.010). Donor fetuses had higher CCO after laser therapy. Higher prelaser CCO in recipient fetuses may indicate more advanced disease. Fetuses who exhibit a decrease in CCO after therapy laser may be at higher risk for perinatal mortality.

Audit of immediate outcomes for MCDA twins following laser therapy for twin-twin transfusion syndrome at the NSW Fetal Therapy Centre.

To audit immediate pregnancy and neonatal outcomes of selective laser photocoagulation of communicating vessels (SLPCV) for twin-twin transfusion syndrome (TTTS) at the New South Wales Fetal Therapy Centre. Retrospective cohort study of 151 TTTS cases undergoing SLPCV between July 2003 and May 2013, evaluating procedural details, delivery and perinatal outcomes. The majority of cases were Stage III at SLPCV (56.9%), although proportion of Stage II SLPCV increased over time (P = 0.03). Survival to hospital discharge of at least one baby was 85.6% and dual survival was 52.5%. Median gestational age at delivery was 32.6 weeks (IQR 29.0-35.0 weeks) with a median of 11.4 weeks (IQR 8.3-14.7) from laser to delivery. Median birthweight was 1792 g (IQR 1288-2233 g), with 75% of babies admitted to the nursery, predominantly secondary to prematurity. Immediate SLPCV complications were in utero fetal demise <1 week postprocedure in 27 fetuses (19.6%) and/or ruptured membranes <1 week postprocedure in 9 fetuses (6.6%). This Australian series shows that local outcomes after SLPCV for stages II-IV TTTS remain equal to the international published literature and have remained stable after an initial learning curve. Women were more likely to be Stage II rather than III in the more recent years. However, this does not appear to be attributable to altered referral patterns.

150: USFetus surgical benchmarks of selective laser therapy for twin-twin transfusion syndrome

150: USFetus surgical benchmarks of selective laser therapy for twin-twin transfusion syndrome

Fetoscopic laser therapy for twin-twin transfusion syndrome: beyond current gestational age limits.

Both "early" (< 16 weeks' gestation) and "late" (> 26 weeks' gestation) presentations of twin-twin transfusion syndrome (TTTS) are rare and challenging complications of monochorionic/diamniotic twin pregnancies. Growing evidence suggests that fetoscopic laser therapy for both "early" and "late" TTTS is feasible, safe, and yields similar outcomes to cases treated between 16 and 26 weeks' gestation. We suggest reevaluation of conventional gestational age guidelines for laser therapy for TTTS.

Short and medium-term outcomes of live-born twins after fetoscopic laser therapy for twin-twin transfusion syndromea

To evaluate short and medium term outcomes of children born of monochorionic pregnancies complicated by twin-twin transfusion syndrome treated by fetoscopic laser surgery. This was a retrospective observational study performed between May 2007 and 2012. Neonatal data was from 45 patients under 5 years of age. The prospective observational study was of the neurologic outcome of these children using the Ages and Stages Questionnaire (ASQ), 2nd edition, French version, at up to 5 years of age. Neurologic assessment at discharge from maternity unit was normal for 41 infants (93.2%). Logistic regression suggested that the risk of neurosensory sequelae was significantly related to the status of donor [odds ratio=4.62 (1.18; 18.0)] and significantly preterm birth <32 weeks of gestation [odds ratio=5.50 (1.38; 21.9)]. Eleven questionnaires were considered abnormal (31.1%). Two children presented a severe neurologic abnormality (5.7%). There was no significant correlation between any area of the questionnaire and status at birth (donor or recipient). The data from our cohort, particularly as regards neurologic outcome, were satisfactory and concordant with previously published results. The use of the ASQ as a screening tool for neurologic outcome in children is original, which allowed in our cohort to highlight early neurological disorders.

Regionalisation of fetal medicine in Australia and New Zealand

Regionalisation of fetal medicine in <scp>A</scp>ustralia and <scp>N</scp>ew <scp>Z</scp>ealand

Fetoscopic guide laser therapy for twin–twin transfusion syndrome

Twin-twin transfusion syndrome (TTTS) affects 1 in 10 monochorionic (MC) twin pregnancies, and is the most important cause of death and neurological injuries in live-born fetuses in MC twins. Since one randomized trial demonstrated that fetoscopic laser photocoagulation achieved better outcomes than serial amniodrainage for all stages of TTTS before 26 weeks, centers of fetoscopic laser therapy for TTTS are currently being initiated worldwide. This review discusses the history, instruments and techniques of fetoscopic laser photocoagulation for TTTS. Finally, we report our current outcomes of TTTS treated by fetoscopic laser photocoagulation in a single center in Taiwan.

Fetoscopic laser therapy for twin-twin transfusion syndrome before 17 and after 26 weeks' gestation

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. We conducted a single center, retrospective analysis of 325 consecutive pregnancies that underwent fetoscopic laser therapy for severe TTTS. 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. 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.