NV Organon, Clinical Development Department, P.O.Box 20, 5340 BH, Oss, The Netherlands
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Abstract |
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Key words: controlled ovarian stimulation/ganirelix/neonatal outcome/obstetrical outcome/pregnancy
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Introduction |
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Most data on children born after IVF relate to pregnancies established after ovarian stimulation with gonadotrophins and concurrent GnRH agonist treatment to prevent premature LH surges. Higher risks as compared with natural pregnancies are reported in pregnancies after IVF primarily owing to growth retardation and preterm birth. Although this can be explained by the high multiple pregnancy rates in IVF pregnancies (2530%), an increased rate of small for gestational age and preterm birth children is reported in singleton IVF pregnancies as compared with natural singleton pregnancies after adjustment for potential bias (Buitendijk et al., 2000; Koudstaal et al., 2000a
,b
). Overall, there is no evidence of an excess risk of congenital malformations in children born after IVF and the absolute risk of a child with a congenital malformation in association with IVF is small (Ericson and Källén, 2001
).
Little information is available on the safety for children born after ovarian stimulation with new stimulation protocols including GnRH antagonists. It can be hypothesized that inducing a higher risk of an impaired obstetrical and perinatal outcome by administering ganirelix is unlikely. The terminal half-life of ganirelix is relatively short (~13 h) with a rapid recovery of hormone levels within 2 days after the last injection and, therefore, exposure of the embryo after transfer, which occurred at least 2 days after the last dosing, is unlikely (Oberyé et al., 1999a,b
). Indeed, a preliminary report on the safety of ganirelix based on the results of a dose-finding study (included in this manuscript) presented reassuring obstetrical and neonatal data (Olivennes et al., 2001
). Furthermore, non-comparative data presented in a recent report on another GnRH antagonist, cetrorelix, showed no safety concerns regarding pregnancy and health status of children after 2 years follow-up (Ludwig et al., 2001
).
In this study, the results of an analysis of pooled data of all follow-up trials comparing obstetrical and neonatal outcome from ongoing pregnancies >16 gestational weeks after controlled ovarian stimulation for conventional IVF or ICSI as compared with GnRH agonist in a long protocol are presented to substantiate the safety of ganirelix for pregnant women and their newborn babies.
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Materials and methods |
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Subjects
In total, 474 subjects with an intact pregnancy of at least 16 weeks were eligible, 340 after treatment with ganirelix and 134 after treatment with a GnRH agonist. Only data after fresh embryo transfer were included, except for the single centre, multiple-cycle phase 3 trial in which frozen embryos were also allowed. All subjects completed the follow-up period. Overall, 45 clinical trial sites (see Appendix) were involved, and 11 sites participated in two trials.
Treatment
Regimen and dosing were extensively discussed in the previously referred publications. Briefly, in the ganirelix group, stimulation with rFSH was started on day 2 or 3 of the natural cycle (150 IU rFSH (Puregon, NV Organon, Oss, The Netherlands) or 225 IU rFSH (Follistim, Organon Inc., West Orange, NJ, USA) fixed for 5 days, thereafter with dose adjustments based on the individual's ovarian response. Ganirelix (0.25 mg, daily, s.c.; Orgalutran, NV Organon) was administered from day 6 onwards up to and including the day of HCG. In the agonist group, dosing of either leuprolide acetate (1.0 mg Lupron, daily, s.c.; TAP Pharmaceuticals, Chicago, IL, USA), buserelin (0.6 mg Suprecur, daily, intranasally; Hoechst, Germany) or triptorelin (0.1 mg Decapeptyl, daily, s.c.; Ferring AB, Sweden) was started in the mid-luteal phase of the preceding cycle. After 2 weeks and confirmation of pituitary down-regulation, stimulation with rFSH as described for the ganirelix group was started. Induction of final oocyte maturation was triggered with HCG (10 000 IU Pregnyl; NV Organon/Organon Inc.) if at least three follicles 17 mm were documented by ultrasonography. In all protocols, oocyte retrieval was performed 3036 h after HCG administration followed by conventional IVF or ICSI. No more than three embryos were to be transferred at 25 days after oocyte retrieval. Luteal support was given according to the investigators' routine practice.
Assessments
Information about pregnancy including results of prenatal diagnostic procedures and delivery was collected either directly at the trial site or through a standard questionnaire if the subject's obstetric care was provided by the referring medical doctor or another physician. Information about the children was gathered at birth and, optionally, until 8 weeks after birth.
Congenital malformations documented prenatally, at birth or at follow-up until 8 weeks post-partum were classified by a single person at the Drug Safety Surveillance Department of NV Organon, using two different definitions for major malformations. Definition A refers to a major congenital malformation as a condition that reduces viability or compromises the quality of life and requires medical treatment. Definition B, which was used in other IVF follow-up programmes (Wisanto et al., 1995; Bonduelle et al., 1996
, 1999
) refers to a major congenital malformation as a condition that causes functional impairment or requires surgical intervention. All remaining congenital malformations were considered minor. Malformations and anomalies were considered synonymous with structural abnormality (Smith, 1975
; Holmes, 1976
).
Statistics
Data were summarized using descriptive summary statistics (mean, SD), unadjusted for centre. Relevant non-dichotomous data have been statistically compared using analysis of variance. Dichotomous data were compared per singleton, twin or triplet with a Fisher exact test. The Cochran Mantel Haenszel analysis with weighing over the number of liveborns was used for the overall result. Differences were considered to be statistically significant when P < 0.05.
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Results |
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Average (± SD) age of the women included was 31.4 ± 3.8 years in the ganirelix group and 31.3 ± 4.1 years in the agonist group. The majority of the women included were nulliparous, 263 (77.4%) of the women in the ganirelix group and 105 (78.4%) in the agonist group.
In the ganirelix group, there were 258 (75.9%) singleton, 72 (21.2%) twin and 10 (2.9%) triplet pregnancies; in the agonist group, there were 91 (67.9%) singleton, 36 (26.9%) twin and seven (5.2%) triplet pregnancies at 16 weeks gestation. A slightly higher multiple pregnancy rate was observed in the agonist group (32.1 versus 24.1%, Table I), but the difference was not statistically significant.
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Incidence and nature of complications during pregnancy did not differ between the two groups (Table II). In each group, ~40% of women with a singleton pregnancy reported at least one complication. In the subjects with multiple pregnancy, the incidence of pregnancies with at least one complication was substantially higher as compared with subjects with a singleton pregnancy and did not differ statistically significantly between the groups (68.3% in the ganirelix group and 74.4% in the agonist group).
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Delivery
The mode of delivery in the two groups did not differ significantly, as shown in Table III. One-third of women with singleton pregnancies in both groups delivered by Caesarean section, 85 of 252 (33.7%) and 30 of 92 (32.6%) in the ganirelix and agonist group respectively. In subjects with twins, the Caesarean section rate was at least twice as high as compared with singleton pregnancies [53 of 70 (75.7%) in the ganirelix group and 22 of 33 (66.7%) in the agonist group] and all triplets were delivered by Caesarean section.
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Comparing the singleton and multiple pregnancies in both treatment groups, the duration of pregnancy was shorter, the overall incidence of preterm births considerably higher and the mean birth weight lower with higher levels of multiplicity. Furthermore, the incidence of (very) low birth weight was higher, and deliveries by Caesarean section were substantially higher with higher levels of multiplicity.
Congenital malformations
Congenital malformations were observed in 32 of 424 (7.5%) fetuses 26 gestational weeks in the ganirelix group and in 10 of 181 (5.5%) in the agonist group (Table IV
, Table V
contains an itemized list of all malformations). The figures do not include two cases of chromosomal abnormality without detectable anomalies at birth: one child (ganirelix group) with 47XYY and one child (agonist group) with a `minor chromosome defect, which is associated with a 5% increased risk of minor heart failure' who did not show any heart abnormality at examination post-partum. The (Mantel-Haenszel) odds ratio, ganirelix versus agonist, was 1.40 [95% confidence interval (CI): 0.672.90].
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The malformation rate, defined as the total number of malformations observed in liveborn children, stillborn children and induced abortions for malformations in relation to the total number of fetuses 26 gestational weeks (EUROCAT, 1993
) was 8.3 (35/424) in the ganirelix group and 5.5 (10/181) in the agonist group, the difference not being statistically significant. Including only major malformations, these malformation rates were 1.9 versus 0.6 applying definition A and 4.5 versus 3.3 applying definition B for the ganirelix and agonist group respectively.
Comparing the IVF procedure and the incidence of all congenital malformations (Table VI), there were no major differences between the two groups in the incidence of congenital malformations in children from pregnancies after ICSI (5.9 and 8.5% for the ganirelix and the agonist group respectively). A non-significant difference was found between the two treatment groups for the incidence of congenital malformations after ICSI versus non-ICSI IVF. In the agonist group, 8.5% in the ICSI group and 3.7% in the non-ICSI group showed congenital malformations, whereas in the ganirelix group the incidence of congenital malformations in the ICSI and non-ICSI group was 5.9 versus 9.1%. No differences were observed between major and minor malformations when comparing treatment and IVF procedure.
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Discussion |
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Although a maximum number of three embryos was allowed for transfer, the overall multiple pregnancy rate across the clinical trial programme was high. Still, the multiple pregnancy rates were in accordance with the multiple pregnancy rate of 2530% with a 3% triplet pregnancy rate reported in the literature (Buitendijk, 1999; ESHRE Capri working group, 2000; Nygren and Andersen, 2001
). Multiple pregnancy is a risk factor for obstetrical complications such as maternal morbidity, prematurity, growth retardation and perinatal mortality (FIVNAT, 1996
). The overall complication rate (at least one complication) was significantly higher in women with multiple pregnancies compared with those with singleton pregnancies, which is in line with data in the literature. However, no differences in pregnancy complications were observed between the two treatment groups in singleton or multiple pregnancies.
Birth characteristics, i.e. mean gestational age, prematurity, mean birth weight and incidence of both low and very low birth weight, did not differ between the two treatment groups with the exception of the overall preterm birth rate in twin pregnancies. The latter was significantly higher in the agonist group, which is most likely a type II error due to the relatively small numbers. The higher overall preterm birth rate observed in the agonist group explains the slightly lower mean gestational age and birth weight in twins after agonist treatment as compared with ganirelix (not statistically significant). From the presented data, it can be seen that the overall high incidence of prematurity was primarily caused by multiple pregnancies. Multiple pregnancy itself is associated with a higher rate of premature birth (Spellacy et al., 1990). In several studies controlled for potential confounding factors (e.g. age, parity, ethnicity, date of delivery), it has been shown that the spontaneous onset of labour in twin pregnancies occurred significantly earlier in IVF than in naturally conceived twin pregnancies and resulted in a significant increase in the incidence of preterm births (Dhont et al., 1997
; Moise et al., 1998
; Buitendijk et al., 2000
; Daniel et al., 2000
; Koudstaal et al., 2000a
). Although the overall preterm birth rate in singleton pregnancies did not differ between the treatment groups, the incidence of prematurity in both groups is also slightly higher than in naturally conceived singleton pregnancies, which varies between 4 and 9% as reported in previous studies (Buitendijk, 1999
; Koudstaal et al., 2000b
). It is unknown whether the increased preterm birth rate both in singleton and multiple pregnancies as compared with naturally conceived pregnancies is caused by ovarian stimulation, the IVF procedure itself, an iatrogenic effect (early intervention by Caesarean section) or by characteristics of the group of patients (e.g. maternal age). In a study comparing the pregnancy outcome of singletons after IVF, cryopreservation and natural conception, the preterm birth rate between IVF cycles with fresh embryo transfer was statistically significantly higher than in the two other groups, those after spontaneously acquired pregnancies and cryopreservation being identical (Wennerholm et al., 1997
). This denotes ovarian stimulation as a potential factor involved; however, additional studies are needed to clarify this.
Mean birth weight and (very) low birth weight did not differ between treatment groups. Some controlled studies indicate that IVF children have a lower mean birth weight and an increased incidence of low birth weight both from singleton and multiple pregnancies as compared with those after natural pregnancies (Koudstaal et al., 2000a,b
), whereas another controlled epidemiological study does not confirm this (Westergaard et al., 1999
). The figures presented here do not deviate from those known from the literature (Bergh et al., 1999
; Westergaard et al., 1999
; Koudstaal et al., 2000a
,b
).
Although there were no differences between the treatment groups, the incidence of Caesarean section is high in singleton and multiple pregnancies as compared with previously published data (FIVNAT, 1996; Westergaard et al., 1999
; Koudstaal et al., 2000a
,b
). On the other hand, comparable data were presented from a single university IVF clinic study (Palermo et al., 1996
) and the Swedish registry (Bergh et al., 1999
). The trials reported here were multicentre and multinational (see Appendix) and, most likely, national differences in indications for Caesarean section employed by obstetricians explain the high overall Caesarean section rate.
Documentation of congenital malformations is hampered by the lack of a gold standard. The incidences of congenital malformations reported in the literature may vary because of inconsistency in the definition or criteria used to classify birth defects. Furthermore, the cut-off point in gestational age may vary. In this analysis, we chose to use 26 gestational weeks, which is the lower limit of premature viability in humans and has been used before in reports also applying definition B (Wisanto et al., 1995; Bonduelle et al., 1996
). Other inconsistencies relate to the exclusion of certain malformations, such as inguinal hernias and/or pyloric stenosis (e.g. the Congenital Malformation Statistics of England and Wales, and the Liverpool Congenital Malformations Statistics), inguinal or umbilical hernia, hydrocoele, and naevus/hemangiomata, or to inclusion of only liveborn infants (Kurinczuk and Bower, 1997
). Another important factor to be considered in comparing data from different studies is whether reporting is based on spontaneous reports from physicians, examination by the obstetrician (followed by a paediatrician if required) as it was done in the trials reported here, or a rigorous examination by an experienced paediatrician following a strict protocol in all children. Meticulousness of post-partum examination will definitely have an effect on the reported incidences. Interpretation of figures, especially when comparing data from different sources, must be done bearing the above in mind. The figures presented for the incidence of total malformations can, therefore, only be compared between groups showing no statistical differences between the GnRH agonist and antagonist group. It should be emphasised that we have presented all birth defects identified regardless of clinical relevance and in the calculation of incidence and malformation rates we have not excluded any reported birth defect. In our first analysis, a strict definition was used (definition A) in differentiating major and minor congenital malformations. A second analysis was performed applying a different, widely used and less strict definition (definition B) because of the lack of a single, globally accepted definition. The figures clearly show how applying a different definition affects the incidences in the subgroups. The incidence of major malformations and the major malformation rate is higher when applying definition B because a surgical procedure even of a clinically irrelevant lesion would classify that lesion as a major malformation. As an example, an inguinal hernia that is treated surgically qualifies as a major malformation, whereas it is considered a delay in normal development despite surgical corrections rather than as a major malformation in other registries (Bonduelle et al., 1996
). No differences between the treatment groups were distinguished, irrespective of the definition used.
Considering limitations in taking published data as a reference, the presented unrestricted data do not differ from those derived from birth registries and follow-up studies reported in the literature. From the Danish IVF Registry (19941995), an overall malformation rate of 4.8% was reported versus a background incidence of 4.6% after correction for potential confounders given the characteristics of the IVF population (Westergaard et al., 1999). A paper presenting data from the Swedish National Birth Registry (19821997) showed an incidence of 5.6% in the IVF population, which was not statistically different from the background incidence after correction for confounders (Ericson and Källén, 2001
). Analysis of data from individual IVF clinics reveals comparable figures. The incidence of major malformations published in a study of 423 ICSI children in Belgium was 3.3% with a major malformation rate of 3.7% (Bonduelle et al., 1996
). An evaluation of a much larger data base (1987 ICSI children) conducted in the same clinic showed an incidence of major malformations of 2.3% and a major malformation rate of 2.9% (Bonduelle et al., 1999
). The figures presented in this paper are in the same order as those of the latter studies, in which the same definition for major malformations, definition B, and malformation rate was employed.
In the relatively small numbers of children with congenital malformations, there was no difference within and between treatment groups comparing conventional IVF and ICSI. In a previous analysis of a large group of children after ICSI, no increased risk was observed in the incidence of malformations either in the overall group or in subgroups separated by sperm origin into ejaculated, epididymal, testicular, fresh or frozen (Bonduelle et al., 1999). Other studies have also not found an increased risk in ICSI children (Palermo et al., 1996
; Tarlatzis and Bili, 1998
; Wennerholm et al., 2000
; Ericson and Källén, 2001
). An excess risk of hypospadias appears to exist in ICSI boys, which is thought to be associated with paternal subfertility and hypospadias (Wennerholm et al., 2000
; Ericson and Källén, 2001
).
The only study published to date on the neonatal outcome of pregnancies established after administering a GnRH antagonist in conventional IVF or ICSI presented data of 232 pregnancies and 227 children. Pregnancies were also accomplished in a phase 2 and phase 3 clinical development programme and follow-up data were available up to 2 years of age (Ludwig et al., 2001). No control group was included and a slightly different system of defining malformations was used. The results indicated that the antagonist protocol had no detrimental effect on pregnancy course, birth characteristics or developmental competence. The findings for pregnancy and neonatal outcome were in line with those presented in this paper.
Reviewing the results of the data presented and the literature on obstetric and neonatal outcome after conventional IVF or ICSI, we conclude that a controlled ovarian stimulation protocol including the newly introduced GnRH antagonist ganirelix has been shown to be safe for pregnant women and their newborn babies.
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Appendix |
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Notes |
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References |
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Submitted on February 26, 2002; accepted on May 1, 2002.