Transabdominal Amnioinfusion Research Articles

Amnioinfusion compared with expectant management in oligohydramnios with intact amnions in the second and early third trimesters.

Treatment of oligohydramnios in the mid-trimester is challenging, because of the high incidence of adverse perinatal outcomes mainly due to bronchopulmonary dysplasia. Antenatal amnioinfusion has been proposed as a possible treatment for oligohydramnios with intact amnions, but there are few relevant studies. This study aimed to evaluate the effectiveness of transabdominal amnioinfusion in the management of oligohydramnios without fetal lethal malformations in the second and early third trimesters. It is a historical cohort study. A total of 79 patients diagnosed with oligohydramnios at 18-32 weeks gestation were enrolled. In the amnioinfusion group (n = 39), patients received transabdominal amnioinfusion with the assistance of real-time ultrasound guidance. In the expectant group (n = 41), patients were treated with 3000 mL of intravenous isotonic fluids daily. The perioperative complications and perinatal outcomes were analyzed. Compared with the expectant group, the delivery latency was significantly prolonged, and the rate of cesarean delivery was significantly reduced in the amnioinfusion group (p < 0.05). Although the rate of intrauterine fetal death was significantly reduced, the incidence of spontaneous miscarriage, premature rupture of membranes (PROMs), and threatened preterm labor were significantly higher in the amnioinfusion group than in the expectant group (p < 0.05). There was no significant difference in terms of perinatal mortality (28.9% vs. 41.4%, p > 0.05). Multivariate logistic regression revealed that amnioinfusion (odds ratio [OR] 0.162, 95% confidence interval [CI] 0.04-0.61, p = 0.008) and gestational age at diagnosis (OR 0.185, 95% CI 0.04-0.73, p = 0.016) were independently associated with neonatal adverse outcomes. Further subgrouping showed that amnioinfusion significantly reduced the frequency of bronchopulmonary hypoplasia for patients ≤26 weeks (26.7% vs. 75.0%, p = 0.021). The rates of other neonatal complications were similar in both groups. Amnioinfusion has no significant effect on improving the perinatal mortality of oligohydramnios in the second and early third trimesters. It may lead to a relatively high rate of PROM and spontaneous abortion. However, amnioinfusion may significantly improve the latency period, the rate of cesarean delivery, and neonatal outcomes of oligohydramnios, especially for women ≤26 weeks with high risk of neonatal bronchopulmonary hypoplasia.

Perinatal and neonatal outcomes of women with very early preterm premature rupture of membranes treated via serial transabdominal amnioinfusion and expectant management: Experience of a tertiary referral center in Turkey.

We compared the outcomes of serial transabdominal amnioinfusion and expectant management on the perinatal and neonatal outcomes of pregnancies complicated with very early preterm premature rupture of membranes (PPROM). We retrospectively reviewed the records of patients with very early PPROM admitted to the University of Inonu School of Medicine from 2014 to 2019. All such patients received comprehensive counseling on the possible prognoses; all were offered pregnancy termination, expectant management, and serial transabdominal infusion. Sixty-three women met the inclusion criteria; 36 were assigned to the expectant management group and 27 were assigned to the amnioinfusion group. The median delivery latency and the gestational age at delivery were significantly higher in the amnioinfusion than the expectant management group [35 (11-90), 14 (7-48), p < 0.001; 27.6 (22.1-34.0), 22.3 (19.0-26.5), p <0.001, respectively]. Serial transabdominal amnioinfusion was associated with significantly less neonatal mortality than expectant management (29.6 vs 83.3%, p <0.001). Multivariate binary logistic regression showed that the odds of neonatal mortality were 6.12 times higher among neonates in the expectant management group compared to that of the serial transabdominal amnioinfusion group after adjusting for potential confounders. Severe neonatal morbidities were significantly more common in the expectant management group than in the amnioinfusion group (p =0.011). The present study has demonstrated a significant positive effect of serial transabdominal amnioinfusion procedure on latency period and neonatal morbidity and mortality in pregnant women complicated with very early PPROM.

Transabdominal amnioinfusion: An evaluation of its adverse events

ObjectiveTransabdominal amnioinfusion is beneficial in oligohydramnios, which has high fetal mortality and does not improve with observation alone. However, there are few reports on the maternal adverse events of transabdominal amnioinfusion. This study aimed to evaluate the adverse events of amniocentesis with transabdominal amnioinfusion. Study designThis study is a retrospective cohort study at a single tertiary perinatal center in Japan. A total of 313 procedures in 126 patients who underwent amniocentesis for transabdominal amnioinfusion at our tertiary perinatal institution were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE). Adverse events were retrospectively examined using a 5-grade evaluation based on the CTCAE. Procedurally, a 21–23-G percutaneous transhepatic cholangiography drainage (PTCD) needle was advanced under ultrasound guidance into the amniotic fluid cavity with a gravity-fed infusion of warm saline solution. ResultsNo maternal deaths were recorded. Only two maternal/fetal adverse events occurred, and grade 4 fetal adverse events requiring pregnancy termination were observed in seven cases. Fetal death occurred in five cases, all with severe oligohydramnios and premature rupture of the membranes. No placental abruption or bleeding occurred before or after delivery. ConclusionAdverse events during transabdominal amnioinfusion were successfully analyzed using CTCAE. We also provided new terminology for evaluating adverse events during amnioinfusion. Our results may encourage obstetricians to perform amnioinfusion in difficult situations, with less concern for severe maternal or fetal adverse events.

Changes in the Intra-Amniotic Pressure following Transabdominal Amnioinfusion during Pregnancy

Objective: The aim of the article was to investigate the changes in intra-amniotic pressure following transabdominal amnioinfusion during pregnancy. Design: This retrospective study included 19 pregnant women who underwent transabdominal amnioinfusion during pregnancy to relieve umbilical cord compression and improve the intrauterine environment or to increase the accuracy of ultrasonography. Materials and Methods: We measured and analyzed the changes in intra-amniotic pressure, single deepest pocket, and the amniotic fluid index before and after amnioinfusion. We also determined the incidence of maternal or fetal adverse events, such as preterm premature rupture of membranes, preterm delivery, fetal death within 48 h, placental abruption, infection, hemorrhage, and peripheral organ injury. Results: A total of 41 amnioinfusion procedures were performed for 19 patients. The median gestational age during the procedure was 24.3 weeks. The median volume of the injected amniotic fluid was 250 mL. The median single deepest pocket and amniotic fluid index after amnioinfusion were significantly higher than those before amnioinfusion (4.0 cm vs. 2.65 cm; p < 0.001 and 13.4 cm vs. 6.0 cm; p < 0.001). However, the median (range) intra-amniotic pressure after amnioinfusion was not significantly different compared to that before amnioinfusion (11 mm Hg vs. 11 mm Hg; p = 0.134). Maternal or fetal adverse events were not observed following amnioinfusion. Conclusion: Intra-amniotic pressure remained unchanged following amnioinfusion. The complications associated with increased intra-amniotic pressure are not likely to develop if the amniotic fluid index and/or single deepest pocket remains within the normal range after amnioinfusion. Studies of groups with and without complications are warranted to clarify the relationship between the intra-amniotic pressure and incidence of complications.

Amnioinfusion in severe oligohydramnios with intact membrane: an observational study

Objective The objective of this article was to evaluate the outcome of transabdominal amnioinfusion in pregnant patients with oligohydramnios. Method This is a prospective observational study involving 80 cases of oligohydramnios treated with transabdominal amnioinfusion guided by ultrasound, in the period between 2011 and 2016. The patients were treated in two centers; however, all the procedures were performed by the same operator. Results The mean gestational age at the first treatment was 24 weeks. Some patients received more than one amnioinfusion. The mean interval between the first infusion and delivery was 31 d. Perinatal and neonatal mortalities were 45% and 35%, respectively. There were five cases of chorioamnioitis and in majority of the cases; the final diagnosis was made after amnioinfusion. Conclusion The procedure has been proven to be very safe. The result showed a high perinatal mortality which was not surprising, as these pregnancies were complicated by a major fetal malformation. Significantly, this study showed that the diagnosis accuracy of the concomitant congenital fetal malformation was significantly improved. The diagnosis accuracy had a major impact on the management of patients, especially the mode of delivery.

Child outcomes after amnioinfusion compared with no intervention in women with second-trimester rupture of membranes: a long-term follow-up study of the PROMEXIL-III trial.

ObjectiveTo assess the effect of transabdominal amnioinfusion or no intervention on long‐term outcomes in children born after second‐trimester prelabour rupture of the membranes (PROM between 16+0/7–24+0/7 weeks) and oligohydramnios.PopulationFollow up of infants of women who participated in the randomised controlled trial: PPROMEXIL‐III (NTR3492).MethodsSurviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence. Parents were asked to complete several questionnaires.Main outcome measuresNeurodevelopmental outcomes were measured. Mild delay was defined as −1 standard deviation (SD), severe delay as −2 SD. Healthy long‐term survival was defined as survival without neurodevelopmental delay or respiratory problems.ResultsIn the amnioinfusion group, 18/28 children (64%) died versus 21/28 (75%) in the no intervention group (relative risk 0.86; 95% confidence interval [CI] 0.60–1.22). Follow‐up data were obtained from 14/17 (82%) children (10 amnioinfusion, 4 no intervention). In both groups, 2/28 (7.1%) had a mild neurodevelopmental delay. No severe delay was seen. Healthy long‐term survival occurred in 5/28 children (17.9%) after amnioinfusion versus 2/28 (7.1%) after no intervention (odds ratio 2.50; 95% CI 0.53–11.83). When analysing data for all assessed survivors, 10/14 (71.4%) survived without mild neurodevelopmental delay and 7/14 (50%) were classified healthy long‐term survivor.ConclusionsIn this small sample of women suffering second‐trimester PROM and oligohydramnios, amnioinfusion did not improve long‐term outcomes. Overall, 71% of survivors had no neurodevelopmental delay.Tweetable abstractHealthy long‐term survival was comparable for children born after second‐trimester PROM and treatment with amnioinfusion or no intervention.

P12.07: Evaluation of adverse events of amniocentesis during transabdominal amnioinfusion

P12.07: Evaluation of adverse events of amniocentesis during transabdominal amnioinfusion

EP26.02: The role of transabdominal amnioinfusion during antenatal period

EP26.02: The role of transabdominal amnioinfusion during antenatal period

Amnioinfusion Compared With No Intervention in Women With Second-Trimester Rupture of Membranes: A Randomized Controlled Trial.

To assess the effectiveness of amnioinfusion in women with second-trimester preterm prelabor rupture of membranes. We performed a nationwide, multicenter, open-label, randomized controlled trial, the PPROM: Expectant Management versus Induction of Labor-III (PPROMEXIL-III) trial, in women with singleton pregnancies and preterm prelabor rupture of membranes at 16 0/7 to 24 0/7 weeks of gestation with oligohydramnios (single deepest pocket less than 20 mm). Participants were allocated to transabdominal amnioinfusion or no intervention in a one-to-one ratio by a web-based system. If the single deepest pocket was less than 20 mm on follow-up visits, amnioinfusion was repeated weekly until 28 0/7 weeks of gestation. The primary outcome was perinatal mortality. We needed 56 women to show a reduction in perinatal mortality from 70% to 35% (β error 0.20, two-sided α error 0.05). Between June 15, 2012, and January 13, 2016, we randomized 28 women to amnioinfusion and 28 to no intervention. One woman was enrolled before the trial registration date (June 19, 2012). Perinatal mortality rates were 18 of 28 (64%) in the amnioinfusion group vs 21 of 28 (75%) in the no intervention group (relative risk 0.86, 95% CI 0.60-1.22, P=.39). In women with second-trimester preterm prelabor rupture of membranes and oligohydramnios, we found no reduction in perinatal mortality after amnioinfusion. NTR Dutch Trial Register, NTR3492.

Amnioinfusion for variable decelerations caused by umbilical cord compression without oligohydramnios but with the sandwich sign as an early marker of deterioration

We report prophylactic amnioinfusion (AI) for variable decelerations in umbilical cord compression without oligohydramnios as an early sign of deterioration. We performed a transabdominal AI in cases without oligohydramnios using the ultrasonography findings of umbilical cord compression (i.e. sandwich sign [SWS]) and variable decelerations (VD) in a foetal heart rate. Thirteen cases and 21 AIs were analysed. Nine (69%) cases were of a foetal growth restriction and 4 (31%) had umbilical hyper-coiled cords. VD frequency (p < .0001), umbilical artery pulsatility index (PI) (p < .01) and ductus venous PI (0.66 vs. 0.48; p < .05) significantly decreased, and an umbilical venous (UV) flow volume (121 vs. 197 ml/min/kg; p < .05) significantly increased after AI. The umbilical artery diastolic blood flow abnormalities and UV pulsation improved. In conclusion, AI improves the umbilical cord compression even without oligohydramnios. The SWS is an important marker of deterioration to severe oligohydramnios and latent foetal damage.IMPACT STATEMENTWhat is already known on this subject? Antepartum variable decelerations due to umbilical cord compression are significantly associated with the deceleration in labour. In particular, foetal hypoxia leads to other adverse events such as foetal distress, hypoxic-ischemic encephalopathy, and pulmonary arterial hypertension after birth. Amnioinfusion has been shown to be effective in patients who also have oligohydramnios.What do the results of this study add? Amnioinfusion may be effective in the cases with ultrasonography findings of umbilical cord compression (i.e. sandwich sign) and in cases with variable decelerations in foetal heart rate, but without oligohydramnios.What are the implications of these findings for clinical practice and/or further research? Amnioinfusion may be helpful to prevent adverse events including oligohydramnios and anhydroamnios.

Hypercoiled cord can cause a reversible abnormal Doppler in ductus venosus in cases of fetal growth restriction.

Although an absent or reversed a-wave in ductus venosus (DV-RAV) is reported to be the terminal finding of fetal growth restriction (FGR), we have seen DV-RAV that disappears within a short span of time in some FGR cases with a hypercoiled cord. The purpose of this study was to investigate the relationship between hypercoiled cord and reversible DV-RAV in FGR. This was a retrospective study of 499 FGR cases, including 14 with DV-RAV. Transabdominal amnioinfusion (AI) was performed when oligohydramnios was severe (maximum vertical pocket <2 cm) and/or variable deceleration was detected. DV-RAV that disappeared quickly was defined as 'temporary DV-RAV'. DV-RAV that continued until delivery or fetal death (FD) was defined as 'persistent DV-RAV'. A hypercoiled cord was defined as one with an umbilical coiling index >0.6 antenatally or >0.3 postnatally. Clinical characteristics and clinical courses of the two types of DV-RAV were compared. DV-RAV disappeared after AI in all five cases in which temporary DV-RAV was identified. The incidence of a hypercoiled cord was significantly higher among temporary DV-RAV cases (100%) than among persistent DV-RAV cases (14.3%; P = 0.015). The time from detection of DV-RAV to delivery or FD was significantly longer among temporary DV-RAV cases (4.5 weeks) than among persistent DV-RAV cases (0.7 weeks; P = 0.027). Temporary DV-RAV is suspected to be related to the combination of a hypercoiled cord and oligohydramnios. DV-RAV may not be always be a terminal finding in FGR with a hypercoiled cord.

EP14.09: A hypercoiled cord can cause an atypical ductus venosus Doppler in cases of fetal growth restriction

Although an absent or reversed a-wave in ductus venosus (DV-RAV) is reported to be the terminal finding of fetal growth restriction (FGR), we have seen a DV-RAV that disappears in a short span of time, causing us to reconsider the mechanism of DV-RAV in FGR. This was a retrospective study of 499 FGR cases, including 14 with DV-RAV. Transabdominal amnioinfusion (AI) was performed when oligohydramnios was severe and/or a sign of cord compression was detected. DV-RAV that disappeared in a short span of time was defined as “temporary DV-RAV”. DV-RAV that continued until delivery or fetal death (FD) was defined as “persistent DV-RAV”. The clinical characteristics and clinical courses were compared between the two types of DV-RAV. Temporary DV-RAV was detected in five cases. DV-RAV disappeared after AI in all of the temporary DV-RAV cases. The incidence of a hypercoiled cord was significantly higher in temporary DV-RAV cases than in persistent DV-RAV cases. The time from detection of DV-RAV to delivery or FD was significantly longer in temporary DV-RAV cases than in persistent DV-RAV cases. Temporary DV-RAV may be related to disturbed umbilical cord blood flow. DV-RAV may not be always be a terminal finding in FGR with a hypercoiled cord.

Amnioinfusion for women with a singleton breech presentation and a previous failed external cephalic version: a randomized controlled trial

Purpose: Our trial aimed to assess the effectiveness of amnioinfusion for a second attempt at external cephalic version (ECV). Material and methods: This open randomized controlled trial was planned with a sequential design. Women at a term ≥36 weeks of gestation with a singleton fetus in breech presentation and a first unsuccessful ECV were recruited in two level-3 maternity units. They were randomly allocated to transabdominal amnioinfusion with a 500-mL saline solution under ultrasound surveillance or no amnioinfusion before the second ECV attempt. Trained senior obstetricians performed all procedures. The primary outcome was the cephalic presentation rate at delivery. Analyses were conducted according to intention to treat (NCT00465712). Result: Recruitment difficulties led to stopping the trial after a 57-month period, 119 women were randomized: 59 allocated to amnioinfusion + ECV and 60 to ECV only. Data were analyzed without applying the sequential feature of the design. The rate of cephalic presentation at delivery did not differ significantly according to whether the second version attempt was or was not preceded by amnioinfusion (20 versus 12%, p = .20). Premature rupture of the membranes occurred for 15% of the women in the amnioinfusion group. Conclusion: Amnioinfusion before a second attempt to external version does not significantly increase the rate of cephalic presentation at delivery.

Transabdominal amnioinfusion in the correction of oligohydramnios following twin-to-singleton reduction – A report of two cases

Abstract Background: On rare occasions, elective iatrogenic reduction of a dichorionic twin is performed due to maternal request and in order to improve the perinatal outcome. Materials and methods: Nine twin-to-singleton reductions were identified retrospectively at the Feto-maternal Unit, University of Szeged, Hungary, between December 1997 and June 2015. A post-procedure, routine weekly sonographic scan revealed severe oligohydramnios in two out of the nine cases (22.2%) and amnioinfusion was performed in the mid-trimester to prolong gestation. The fetus survived in one case (11.1%) and the pregnancy continued until preterm birth. Conclusion: A repeated sonographic follow-up for an early diagnosis of oligohydramnios is feasible to avoid miscarriage after artificial embryo reduction.

Возможности и перспективы применения трансабдоминальной амниоинфузии для пролонгирования беременности при преждевременном разрыве плодных оболочек и маловодии

Возможности и перспективы применения трансабдоминальной амниоинфузии для пролонгирования беременности при преждевременном разрыве плодных оболочек и маловодии

Amnioinfusion for chorioamnionitis.

Amnioinfusion for chorioamnionitis.

Is amnioinfusion beneficial for neonates after preterm premature rupture of membranes (PPROM)?

Evidence-Based Answer Transcervical amnioinfusion (TCA) does not appear to improve clinical outcomes in PPROM (SOR: A, systematic review). Transabdominal amnioinfusion (TA) may reduce the risk of neonatal sepsis, pulmonary hypoplasia, and neonatal death, but the evidence is conflicting (no SOR given).

Interventions for helping to turn term breech babies to head first presentation when using external cephalic version.

Interventions for helping to turn term breech babies to head first presentation when using external cephalic version.

Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL – III trial)

BackgroundBabies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome.Methods/DesignWomen with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. Intervention: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, β-error 0.2 and α-error 0.05).DiscussionThis study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure.Trial registrationNTR3492 Dutch Trial Register (http://www.trialregister.nl).

Amnioinfusion in preterm premature rupture of membranes (AMIPROM): a randomised controlled trial of amnioinfusion versus expectant management in very early preterm premature rupture of membranes – a pilot study

Fetal survival is severely compromised when the amniotic membrane ruptures between 16 and 24 weeks of pregnancy. Reduced amniotic fluid levels are associated with poor lung development, whereas adequate levels lead to better perinatal outcomes. Restoring amniotic fluid by means of ultrasound-guided amnioinfusion (AI) may be of benefit in improving perinatal and long-term outcomes in children of pregnancies with this condition. The AI in preterm premature rupture of membranes (AMIPROM) pilot study was conducted to assess the feasibility of recruitment, the methods for conduct and the retention through to long-term follow-up of participants with very early rupture of amniotic membranes (between 16 and 24 weeks of pregnancy). It was also performed to assess outcomes and collect data to inform a larger, more definitive, clinical trial. A prospective, non-blinded randomised controlled trial. A computer-generated random sequence using a 1 : 1 ratio was used. Randomisation was stratified for pregnancies in which the amniotic membrane ruptured between 16(+0) and 19(+6) weeks' gestation and 20(+0) and 24(+0) weeks' gestation. The randomisation sequence was generated in blocks of four. Telephone randomisation and intention-to-treat analysis were used. Four UK hospital-based fetal medicine units - Liverpool Women's NHS Trust, St. Mary's Hospital, Manchester, Birmingham Women's NHS Foundation Trust and Wirral University Hospitals Trust. Women with confirmed preterm prelabour rupture of membranes between 16(+0) and 24(+0) weeks' gestation. Women with multiple pregnancies, resultant fetal abnormalities or obstetric indication for immediate delivery were excluded. Participants were randomly allocated to either serial weekly transabdominal AI or expectant management (Exp) until 37 weeks of pregnancy, if the deepest pool of amniotic fluid was < 2 cm. Short-term maternal, pregnancy and neonatal outcomes and long-term outcomes for the child were studied. Long-term respiratory morbidity was assessed using validated respiratory questionnaires at 6, 12 and 18 months of age and infant lung function was assessed at approximately 12 months of age. Neurodevelopment was assessed using Bayley's Scale of Infant Development II at a corrected age of 2 years. Fifty-eight women were randomised and two were excluded from the analysis owing to termination of pregnancy for lethal anomaly, leaving 56 participants (28 serial AI, 28 Exp) recruited between 2002 and 2009, with annual recruitment rates varying between 2 and 14. Recruitment to the study improved significantly from 2007 with National Institute for Health Research (NIHR) funding. There was no significant difference in perinatal mortality [19/28 vs. 19/28; relative risk (RR) 1.0; 95% confidence interval (CI) 0.70 to 1.43], maternal morbidity or neonatal morbidity. The overall chance of surviving without long-term respiratory or neurodevelopmental disability is 4/56 (7.1%): 4/28 (14.3%) in the AI arm and 0/28 in the expectant arm (0%) (RR 9.0; 95% CI 0.51 to 159.70). This pilot study found no major differences in maternal, perinatal or pregnancy outcomes. The study was not designed to show a difference between the arms and the number of survivors was too small to draw any conclusions about long-term outcomes. It does signal, however, that a larger, definitive, study to evaluate AI for improvement in healthy survival is indicated. The results suggest that, with appropriate funding, such a study is feasible. A larger, definitive, study with full health economic analysis and patient perspective assessment is required to show whether AI can improve the healthy survivor rate.