Hum. Reprod. Advance Access originally published online on May 14, 2008
Human Reproduction 2008 23(8):1808-1814; doi:10.1093/humrep/den155
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Cumulative pregnancy rates after sequential treatment with modified natural cycle IVF followed by IVF with controlled ovarian stimulation
1 Section of Reproductive Medicine, Department of Obstetrics and Gynaecology, University Medical Center Groningen, Groningen, The Netherlands 2 Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, The Netherlands
3 Correspondence address. E-mail: pelinck{at}hotmail.com
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Abstract |
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BACKGROUND: In modified natural cycle IVF (MNC-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH-antagonist together with gonadotrophins in the late follicular phase only. The MNC-IVF is of interest because of its low-risk and patient-friendly profile. The effect of application of MNC-IVF preceding standard IVF with ovarian stimulation on overall results is unknown.
METHODS: This single-center cohort study provides follow-up of an earlier study in which nine cycles of MNC-IVF were offered to 268 patients. Ongoing pregnancy rates and live birth rates, as well as time-to-pregnancy after controlled ovarian stimulation-IVF (COS-IVF) following MNC-IVF, were evaluated.
RESULTS: Actual observed cumulative ongoing pregnancy rates and live birth rates after sequential treatment with MNC-IVF followed by COS-IVF were 51.5 (95% CI: 45.4–57.6) and 50.0% (95% CI: 43.9–56.1) per patient, of which 8.0 and 6.7% were twins. Median time to ongoing pregnancy was 28.8 weeks. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 56.7% (95% CI: 50.7–62.8).
CONCLUSIONS: Sequential treatment with MNC-IVF followed by COS-IVF does not appear to compromise overall success rates, while twin pregnancy rate is low. Because of its patient-friendly and low-risk profile, it seems appropriate to perform MNC-IVF preceding COS-IVF.
Key words: natural cycle/assisted reproduction/ovarian stimulation/cumulative pregnancy rate/BESST
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Introduction |
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Modified natural cycle IVF (MNC-IVF), in which treatment is aimed at the use of the one follicle that spontaneously develops in the natural menstrual cycle, is proposed as an alternative to standard IVF with controlled ovarian stimulation (COS-IVF), either for all patients with ovulatory cycles requiring IVF or ICSI (Rongières-Bertrand et al., 1999
; Vogel et al., 2003; Zhioua et al., 2004; Pelinck et al., 2006) or for specific indications such as poor response to ovarian stimulation or advanced female age (Kadoch et al., 2003; Ubaldi et al., 2003; Weghofer et al., 2004; Elizur et al., 2005). A GnRH-antagonist is used in the late follicular phase of the unstimulated cycle, to prevent untimely LH-surges and ovulations and subsequent cancellation of the cycle. Together with the GnRH-antagonist, gonadotrophins are administered to substitute for the expected fall in FSH levels and as a consequence, estradiol (E2) levels (Rongières-Bertrand et al., 1999). A recent paper addressed the terminology for this approach (Nargund et al., 2007).
Compared to COS-IVF, the efficacy of MNC-IVF seems rather low with pregnancy rates per started cycle of 0.0–18.3% (Rongières-Bertrand et al., 1999; Kadoch et al., 2003; Ubaldi et al., 2003; Vogel et al., 2003; Kolibianakis et al., 2004; Weghofer et al., 2004; Zhioua et al., 2004; Elizur et al., 2005; Pelinck et al., 2006, 2007).
However, MNC-IVF has several advantages. It is a patient-friendly treatment, since medication is administered in a low dose and for a few days only, causing few side effects. Oocyte retrieval is easy and short lasting and can be performed without analgesia since usually only one follicle is aspirated (Ramsewak et al., 1990). Moreover, it is a treatment with a low-risk profile due to the negligible risk of ovarian hyperstimulation syndrome (OHSS) and inherent low multiple pregnancy rate. We found higher birthweights in singletons conceived by MNC-IVF compared with COS-IVF (Keizer et al., 2005). Although this should be confirmed in further studies, it is an important finding since higher birthweights probably reflect better health of newborns. Compared to COS-IVF, MNC-IVF may be cost-effective (Groen et al., 2005). The duration of a treatment cycle is short and treatments are easily repeated in consecutive cycles and therefore, pregnancy rates per time spent by the patient may be acceptable (Pelinck et al., 2007).
Given the advantages of MNC-IVF, it seems a feasible treatment option for patients requiring IVF.
Recently, it has been suggested that the best outcome parameter of IVF treatment is the ongoing pregnancy rate or live birth rate per patient starting treatment, or live birth after a given time period (Fauser et al., 2002; Vail and Gardener, 2003; Heijnen et al., 2004, 2007).
So far, little is known about cumulative pregnancy rates after MNC-IVF. We found cumulative ongoing pregnancy rates of 20.8 and 32.4% after a maximum of three and nine consecutive cycles, respectively, with ongoing twin pregnancy rates of 4.3 and 2.4% (Pelinck et al., 2006, 2007). In our center, MNC-IVF is performed preceding COS-IVF, so full treatment consists of MNC-IVF followed by COS-IVF. No studies describing sequential treatment consisting of MNC-IVF followed by COS-IVF are available.
In the present study, results of MNC-IVF followed by COS-IVF are described in a cohort of patients. Cumulative pregnancy rates per patient were calculated, as well as time-to-pregnancy or end of treatment. Fertilization rates were compared between MNC-IVF and COS-IVF.
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Materials and Methods |
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Patients
For the present study, a cohort of 268 patients who were offered nine cycles of MNC-IVF was evaluated and followed up concerning results of full treatment, consisting of MNC-IVF, followed by COS-IVF if necessary.
Inclusion criteria for this study were female patient age 18–36 years, first IVF treatment ever or after a pregnancy (spontaneously conceived or obtained with COS-IVF), the presence of a regular and proven ovulatory menstrual cycle with a length of 26–35 days and body mass index (BMI: kg/m2) of 18–28. Indications for IVF were tubal pathology, unexplained subfertility, male factor, endometriosis, cervical factor or failed donor inseminations. Patients were not included in the study in case an endometriosis cyst was seen on ultrasound. Patients requiring ICSI because of insufficient semen quality were not included in this study. Patients with male factor or unexplained subfertility had undergone treatment with intra-uterine insemination (IUI) for three to six cycles before starting IVF treatment, as is standard protocol in the Netherlands.
The results of MNC-IVF for these patients have been described in detail recently (Pelinck et al., 2007). All patients who conceived with MNC-IVF who miscarried or experienced an ectopic pregnancy were offered again nine cycles of MNC-IVF. For the present study, results of MNC-IVF treatment following abortion or ectopic pregnancy were added to the previously described data, resulting in some patients undergoing more than nine cycles (Pelinck et al., 2007).
Patients who did not conceive with MNC-IVF after nine cycles or who refrained from further MNC-IVF treatment after 0–8 cycles, were offered COS-IVF.
All patients were followed up completely concerning treatments performed in our center.
End-point in the study was ongoing pregnancy, defined as the presence of an intrauterine gestational sac with fetal heart beat at 12 weeks gestational age. Pregnancy was defined as either the visualization of at least one intrauterine gestational sac or a proven ectopic pregnancy. Live birth was defined as the birth of a living infant after pregnancy duration of at least 24 weeks.
MNC-IVF treatment was offered for free. MNC- and COS-IVF treatments were performed between February 2001 and October 2006. Until January 2004, COS-IVF was fully refunded by the insurance companies for a maximum of three cycles. Owing to a change in refunding policy, from 1st January 2004 onwards, the first COS-IVF treatment cycle was not refunded anymore for part of the patients. Also, medication needed for MNC-IVF and the first COS-IVF cycle was no longer refunded for part of the patients. Second and third COS-IVF cycles, including medication, were fully refunded during the entire study period. Fourth and further COS-IVF cycles were never refunded.
The protocol for the study concerning nine cycles of MNC-IVF was reviewed and approved by the ethical committee of the University Medical Center Groningen, the Netherlands. The part of the study concerning COS-IVF treatment did not require approval of the ethical committee because it concerned standard treatment, data of which were recorded anonymously.
Modified natural cycle
MNC-IVF was performed as described in detail previously (Pelinck et al., 2006). In short, unstimulated cycles were monitored by ultrasound. Medication was started after follicular dominance had spontaneously developed. For the prevention of LH rises, the GnRH-antagonist cetrorelix (Cetrotide®, Serono Benelux BV, the Netherlands) was used in a daily dose of 0.25 mg, starting at a follicle size of 14 mm and given up to and including the day of ovulation triggering. For substitution, recombinant FSH (r-FSH: Gonal-F®, Serono Benelux BV, the Netherlands) was given concomitantly in a daily dose of 150 IU, up to the day of ovulation triggering. Ovulation was triggered at a follicle size of 18 mm (10 000 IU of HCG: Pregnyl®, Organon, the Netherlands) and oocyte retrieval was performed 34 h later. In cycles where a serum LH rise was noticed, planning of oocyte retrieval was cancelled according to the previously described criteria (Pelinck et al., 2006). In cases where at the time of planned oocyte retrieval, unexpected ovulation had occurred and tubes were patent, IUI was performed. Conventional IVF was performed according to standard procedures. Embryo transfer (ET) was performed on the third day after oocyte retrieval. Luteal support consisted of HCG 1500 IU at 5, 8 and 11 days after oocyte retrieval.
COS-IVF
COS-IVF was performed using a flare-up or down-regulation protocol, using triptorelin (Decapeptyl®, Ferring Nederland BV, Hoofddorp, the Netherlands) or leuproreline (Lucrin®, Abbott BV, Hoofddorp, the Netherlands) and r-FSH (Puregon®, Organon, Oss, the Netherlands). Cycles were monitored with ultrasounds and serum E2 levels. When at least half of the dominant follicles were >18 mm, ovulation was triggered by 10 000 IU of HCG (Pregnyl®, Organon, Oss, the Netherlands) and oocyte retrieval performed 36 h later under conscious sedation with fentanyl intravenously. Oocyte retrieval was cancelled in the cases of poor response (<3 large follicles) or of threatening OHSS (E2 levels > 15 nmol/l and/or >20 follicles). Conventional IVF was performed according to standard procedures. In one case where in MNC-IVF, fertilization failure had occurred repeatedly, ICSI was performed. In second and third cycles of COS, ICSI was performed if fertilization failure (<10% of all oocytes fertilized) had occurred in a previous cycle of COS. ET was performed on the second, third or fourth day after oocyte retrieval. Luteal support consisted of progesterone vaginal suppositories 3 x 100 mg/day starting on the day of oocyte retrieval until pregnancy test, or HCG 1500 IU at 5, 7 and 9 days after oocyte retrieval.
Data analysis
Cumulative ongoing pregnancy rate and live birth rate after full treatment, consisting of MNC-IVF followed by COS-IVF, were calculated per patient. Time-to-pregnancy or end of treatment was calculated per patient. End-point in the study was an ongoing pregnancy. For patients who conceived with MNC-IVF or COS-IVF and who miscarried or experienced an ectopic pregnancy, subsequent cycles were included in the analysis for the same patient. Fertilization rates in MNC-IVF and COS-IVF were compared and given in the percentages with 95% CI.
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Results |
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Modified natural cycle
Patient characteristics are shown in Table I. Out of 268 included patients, 27 had undergone COS-IVF leading to a pregnancy before entering the study. Twelve patients refrained from MNC-IVF after inclusion in the study, in two cases because a spontaneous (ongoing) pregnancy had occurred. Three patients started COS-IVF instead of MNC-IVF and seven patients refrained from treatment altogether.
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Results of MNC-IVF are shown in Table II. Overall, a total of 1123 cycles were performed, leading to 112 pregnancies, of which 90 were ongoing beyond 12 week gestational age. Four out of 112 pregnancies were twins (three after double ET (DET) and one after single ET (SET)), of which one miscarried. One pregnancy was interrupted because of severe congenital abnormalities (limb body wall complex) and one pregnancy ended with fetal death at 17 weeks gestation. Eighty-eight pregnancies ended with live birth, of which nine were preterm (<37 week gestational age). Of three ongoing twin pregnancies, two ended preterm. Live birth rate and term live birth rate were thus 34.4 and 30.9%, respectively, per patient starting MNC-IVF.
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Eight patients conceived twice with MNC-IVF. Out of 21 patients whose first pregnancy was not ongoing, 19 patients continued with MNC-IVF (75 cycles, leading to eight pregnancies, of which seven ongoing). The remaining two patients refrained from further treatment. One of these subsequently conceived spontaneously and miscarried.
A total of 17 spontaneous conceptions occurred. One patient proceeded with COS-IVF after spontaneous abortion of spontaneous conception.
Pregnancy rates per patient were not different according to the indication for IVF (Chi square: P = 0.58; data not shown).
In summary, for MNC-IVF, cumulative ongoing pregnancy rate, live birth rate and term live birth rate were 35.2 (95% CI: 29.2–41.1), 34.4 (95% CI: 28.4–40.3) and 30.9% (95% CI: 25.1–36.6), respectively, per patient starting treatment, of which 3.3, 3.4 and 1.3% twins. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 38.3% (95% CI: 32.2–44.4) per patient starting treatment.
Per patient included in the study, cumulative ongoing pregnancy rate, live birth rate and term live birth rate after treatment were 33.6 (95% CI: 27.8–39.4), 32.8 (95% CI: 27.1–38.6) and 29.5% (95% CI: 23.9–35.0), respectively. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 37.3% (95% CI: 31.4–43.2) per patient included in the study.
COS-IVF
Out of 268 included patients, 109 proceeded with COS-IVF, results of which are shown in Table III.
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Eleven patients developed OHSS, of which three were hospitalized for treatment.
Fifty-four pregnancies were obtained, of which 48 were ongoing beyond 12 week gestational age. Of these, five were vanishing twin pregnancies, one twin pregnancy was selectively reduced to singleton because of trisomy 21, seven were ongoing twin pregnancies and 35 were ongoing singleton pregnancies.
One twin pregnancy ended with immature birth at 23 week gestational age and one singleton pregnancy ended with fetal death at 16 week gestational age. Forty-six pregnancies ended with live birth, of which nine were preterm. Of six twin pregnancies ending with live birth, four were delivered preterm. Live birth rate and term live birth rate were thus 42.2 and 33.9%, respectively, per patient starting COS.
Two patients conceived twice with COS. Out of six patients, whose first COS-pregnancy was not ongoing, three continued with COS-IVF treatment (four cycles, leading to one singleton ongoing pregnancy and one vanishing twin). One patient, whose COS-pregnancy miscarried, subsequently conceived naturally.
A total of seven spontaneous conceptions occurred after COS-IVF (one abortion, two ectopic and four ongoing). One patient continued with COS-IVF after spontaneous conception of an ectopic pregnancy.
Pregnancy rates per patient were not different according to indication for IVF (Chi square: P = 0.75; data not shown).
In summary, for COS-IVF, cumulative ongoing pregnancy rate, live birth rate and term live birth rate were 44.0 (95% CI: 34.5–53.5), 42.2 (95% CI: 32.7–51.7) and 33.9% (95% CI: 24.9–43.0), respectively, per patient starting treatment, of which 14.6, 13.0 and 5.4% were twins. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 47.7% (95% CI: 38.1–57.3) per patient.
Results of sequential treatment of MNC-IVF followed by COS-IVF
Of all patients included in the study, cumulative ongoing pregnancy rate, live birth rate and term live birth rate were 51.5 (95% CI: 45.4–57.6), 50.0 (95% CI: 43.9–56.1) and 43.3% (95% CI: 37.2–49.3), respectively, per patient after MNC-IVF followed by COS-IVF. Of these, 8.0, 6.7 and 2.6% were twins. Including treatment-independent pregnancy rates occurring before and after treatment, cumulative ongoing pregnancy rate was 56.7% (95% CI: 50.7–62.8), of which 6.6% were twins.
Actual observed cumulative ongoing pregnancy rates according to cycle number of MNC-IVF and COS-IVF are shown in Fig 1a and b.
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Actual observed cumulative ongoing pregnancy rates according to treatment time period are shown in Fig. 2. Cumulative ongoing pregnancy rate was 38.8% (95% CI: 32.9–44.8) and 51.5% (95% CI: 45.4–57.6) after one and two years of treatment, respectively. Fourteen ongoing pregnancies occurred after this period (one after MNC-IVF, ten after COS-IVF and three spontaneous conceptions). The median time of treatment was 34.1 (0–220) weeks for all patients included in the study. The median time to ongoing pregnancy was 28.8 (0–220) weeks.
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Fertilization rates
Of patients who proceeded with COS-IVF after unsuccessful MNC-IVF, fertilization rates after MNC and COS with conventional IVF were compared. Of 109 patients who underwent COS-IVF, in 32 (29.4%) ICSI was performed, in one case in the first COS-cycle and in 31 cases after fertilization failure (<10% of all oocytes fertilized) in a COS-cycle.
In the first cycle with successful oocyte retrieval in patients undergoing COS with conventional IVF, fertilization failure occurred in 25.3% (95% CI: 16.0–34.6). In those patients where none of the oocytes had fertilized in MNC, fertilization failure occurred in 48.0% (95% CI: 28.0–68.0) of first COS-cycles. In those patients where all oocytes had fertilized in MNC, fertilization failure occurred in 9.1% (95% CI: 0.92–19.1) of first COS-cycles.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionFundingAcknowledgementReferences |
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In the present study, results of sequential treatment with MNC-IVF followed by COS-IVF were studied and, including treatment-independent pregnancies, a cumulative ongoing pregnancy rate of 56.7%, of which 6.6% twins, was found.
Cumulative ongoing pregnancy rates were 38.8 and 51.5%, respectively, after 1 and 2 years of treatment. The number of ongoing pregnancies obtained within 1 year seems to be somewhat lower than those found in a study comparing minimal stimulation (gonadotrophins started on day 5 of the cycle and GnRH-antagonist used for LH-suppression) to standard stimulated IVF, in which 46.8% ongoing pregnancies were found after minimal stimulation IVF with SET and 51.8% after standard stimulated IVF with DET (Heijnen et al., 2007). In our study, treatment time is somewhat lengthened because of the inclusion of patients restarting treatment after an abortion or ectopic pregnancy, and also due to some waiting time before starting COS-IVF, caused by limitations in laboratory capacity.
We found a live birth rate after sequential treatment with MNC-IVF and COS-IVF of 50.0%. This seems to be in accordance with reported cumulative live birth rates of 35.7–59.1% found after full treatment with COS-IVF only (Goverde et al., 2000; Witsenburg et al., 2005; Elizur et al., 2006). However, the multiple pregnancy rate in our study (6.7%) is substantially lower than the reported multiple pregnancy rate of 21.2–25.7% in these studies (Goverde et al., 2000; Witsenburg et al., 2005). The live birth rate after full treatment may be slightly underestimated as we did not register if patients underwent treatment elsewhere after leaving our center.
In our opinion therefore, the application of sequential treatment with MNC-IVF followed by COS-IVF if necessary is a realistic strategy. This way, not only a large proportion of patients is spared the risk of OHSS and the discomfort of COS, but also the overall multiple pregnancy rate is substantially reduced.
On the other hand, in COS-IVF, OHSS does not occur frequently and multiple pregnancy rates can be further reduced by applying SET more frequently (Tiitinen et al., 2003; Gordts et al., 2005; De Neubourg and Gerris, 2006). MNC-IVF is a patient-friendly treatment but also has several drawbacks. Compared to COS-IVF, a higher number of MNC-cycles are needed to obtain comparable pregnancy rates. Although the possibility of a quicker succession of treatment cycles is beneficial in MNC-IVF, repeated visits to the clinic and frequent disappointments due to cancellation of oocyte retrieval, unsuccessful oocyte retrieval, fertilization failure and failure to reach ET are burdensome for patients. Unfortunately, formal studies on quality of life in MNC-IVF are lacking, but studies on natural cycle IVF without the use of GnRH-antagonists show that patients seem to prefer natural cycle IVF over stimulated IVF, based on a preference for simplicity and short duration of treatment cycles (Højgaard et al., 2001) or anxiety for hormone injections (Pistorius et al., 2006).
In the present study, an unselected group of patients aged less than 37, reflecting a good prognosis population, was studied and results seem favourable. Further studies should investigate whether MNC-IVF is also feasible in patients of higher age and whether MNC-IVF is indeed appropriate for all patients, or should only be applied in a selection of patients with specific characteristics. In certain situations, like a history of OHSS, or patients opposed to the generation of spare embryos, MNC-IVF seems to be preferable over COS-IVF in all cases. Also poor responders to COS are likely to benefit from MNC-IVF, since these patients have poor oocyte yield and low ET rate with COS and considering cumulative pregnancy rates, may benefit from a quicker succession of treatment cycles in MNC-IVF. In studies comparing MNC-IVF with COS-IVF in poor responders, reported pregnancy rates per cycle were similar (Weghofer et al., 2004; Elizur et al., 2005).
It is unclear that what should be the maximum number of cycles of MNC-IVF to be performed. In a previous study with the same cohort of patients as described in the present study, we found the occurrence of a cancellation of oocyte retrieval and failure to reach ET to be repeating phenomena in further cycles, although this was not reflected in a lower pregnancy rate. Fertilization failure also was found to be a repeating phenomenon, and an associated (although not statistically significant) lower pregnancy rate was found (Pelinck et al., 2007). The number of cycles to be performed before COS-IVF should therefore be individualized, taking into account the results of previous cycles.
In the present study, we found fertilization failure in MNC to be predictive of fertilization failure in COS. Performing ICSI in patients showing fertilization failure in MNC-IVF probably would improve success rates.
In conclusion, sequential treatment with MNC-IVF followed by COS-IVF does not appear to compromise overall success rates, while twin pregnancy rate is very low. Because of the patient-friendly and low-risk profile of MNC-IVF, this seems an appropriate strategy.
Comparative studies on MNC-IVF and COS-IVF are warranted. Such a study should evaluate effectiveness, cost-effectiveness and risks of either treatment modality, but also focus on quality of life and patients' preferences and include time to pregnancy as an end-point.
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This study was supported by a grant from the University Medical Center Groningen, Groningen, the Netherlands and from ZonMw, the Netherlands (grant number 945-02-002). Part of these data was presented at the 23rd annual meeting of ESHRE, July 2007, Lyon, France (P-322).
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Acknowledgement |
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The authors wish to thank all patients for their participation in this study and all personnel at the IVF-department for their enthusiastic contribution.
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References |
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Submitted on November 22, 2007; resubmitted on February 9, 2008; accepted on March 14, 2008.
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