1 Hôpital Antoine Béclère, Service de Gynecologie-Obstétrique 157, Clamart, France, 2 NV Organon, Oss, The Netherlands and 3 Dutch-speaking Brussels Free University, Brussels, Belgium
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Abstract |
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Key words: congenital malformations/GnRH antagonist/infertility treatment/ovarian stimulation/perinatal outcome
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Introduction |
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Although GnRH agonist have been proved to be safe and effective, these compounds have intrinsic disadvantages, including initial flare-ups requiring 23 weeks pretreatment, and the relatively high therapeutic dose of FSH required. Recently, new GnRH antagonists have been proven to be safe and effective, allowing them to be used in general practice. GnRH antagonists have the advantage of rapid, profound and reversible suppression of the pituitarygonadal axis. Even though studies in animals exposed to therapeutic doses of GnRH antagonists did not demonstrate any adverse outcomes among the offspring, careful examination of pregnancy outcome obtained in humans is mandatory. Perinatal outcome and malformation rate are the first available elements of such follow-up, which is required for every new drug introduced into clinical practice. The aim of such follow-up is mainly to exclude a possible increased risk of abnormalities, since there is no reason to believe that GnRH antagonist treatment would be less safe than GnRH agonist treatment, either for mothers or their offspring.
In this first follow-up study, women who became pregnant in a double-blind, multicentre, randomized dose-finding study (The Ganirelix Dose-finding Study Group, 1998) of the GnRH antagonist ganirelix (Orgalutran®) were followed during their pregnancy, and the data concerning neonatal outcomes, including congenital malformations, were collected.
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Materials and methods |
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Study design
This was an open, prospective follow-up study. Information on the course of the pregnancy and neonatal outcome was obtained from the obstetrical files of patients. If the patient received gynaecological care in another hospital other than the IVF clinic, the referring gynaecologist collected the requested data.
Assessments
During pregnancy follow-up, data were collected on the outcome of prenatal diagnosis (if any), on complications during pregnancy or delivery, on the mode of delivery and on neonatal outcome. Data concerning major complications during pregnancy, date of delivery, mode of delivery and number of newborns were requested. For each newborn, data were obtained concerning the date of birth, gender, body weight and length, head circumference, Apgar score (measured 1 and 5 min after birth), result of physical examination and congenital malformations.
Statistical analysis
All data were presented using descriptive summary statistics. The pregnancy of two subjects with a spontaneous reduction resulting in a singleton pregnancy was analysed as a singleton pregnancy; two triplets who both reduced to twins were analysed as twin pregnancies.
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Results |
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Complete information was obtained for 67 of the 68 pregnant patients. The pregnancies included 51 singletons (76.1%), 11 twins (16.4%) and five triplets (7.5%). No relevant differences were observed between patients having a singleton or a multiple pregnancy (twins and triplets) with respect to age, duration of ganirelix treatment, or total amount of ganirelix injected (data not presented). Overall, ICSI was performed in 42% of the patients. In the multiple pregnancy group, the use of ICSI as type of assisted reproductive treatment was greater as compared with the singleton pregnancy group (69 versus 33%).
Complications during pregnancy and delivery
The overall miscarriage rate was 9% (6/67). One patient had a spontaneous abortion in week 19, and another patient reported an intrauterine fetal death in week 27. Hence, 96.7% of patients (59/61) with an ongoing pregnancy delivered at least one live-born infant.
Six patients with a multiple pregnancy had a reduction in the number of fetuses. In five cases the reduction was spontaneous, and included two vanishing twins and three triplets which reduced to twins. One triplet pregnancy was selectively reduced to a twin pregnancy.
Apart from the miscarriages and fetus reductions, the most frequent (>5%) adverse events recorded were vaginitis (6.0%), anaemia (6.0%), premature labour (7.5%), premature uterine contractions (6.0%) and fetal distress (6.0%). For 16 patients, the adverse event led to hospitalization. Of these events, only three were not related to the state of pregnancy; one patient with gastroenteritis, one with uterine fibromyoma, and one with thrombocytopoenia. All patients, except the patient with uterine fibromyoma, recovered from the event.
The main obstetrical and delivery complications are listed in Table I. Spontaneous vaginal delivery occurred in 41.3% of the singleton pregnancies, and in 7.7% of the multiple pregnancies. Elective Caesarean section was performed in 12 out of 19 singleton pregnancies. The overall incidence of Caesarean sections was 41.3 and 84.6% of the singleton and multiple pregnancies respectively.
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Congenital malformations
Among congenital malformations in the offspring, one was major and seven were minor. The major malformation was seen in a baby boy with exomphalos (see Prenatal diagnosis) and macroglossia diagnosed with BeckwithWiedemann syndrome. The baby underwent surgery 3 days after birth and hence recovered from exomphalos. DNA testing of the baby and his parents was not possible since the family moved away without notification.
The seven minor malformations seen in five infants were torticollis, asymmetric head shape, naevus, skin tags, talipes and pyloric stenosis and sacral sinus.
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Discussion |
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In this study the overall incidences of obstetrical complications, perinatal outcome and congenital malformations in patients exposed to recombinant FSH and ganirelix are presented, regardless of whether IVF or ICSI was performed, since a large comparative analysis including more than 2800 children per procedure could not reveal any difference in birth weight, low birth weight, perinatal mortality rate or malformation rates following IVF or ICSI (Bonduelle, 2001; data presented at Sixth International Symposium on GnRH analogues). The incidences presented in the current study were comparable with those reported in larger, more recent follow-up studies, and values observed for gestational age, birth weight and sex ratio were also comparable with previously published reports (MRC, 1990; Rufat et al., 1994
; Bergh et al., 1999
; Loft et al., 1999
; Westergaard et al., 1999
).
One major malformation among 73 children (1.4%) is within the expected figure of major malformation (24%) in the ICSI and IVF population (Bonduelle et al., 1999; Westergaard et al., 1999
; Wennerholm et al., 2000
). The BeckwithWiedemann syndrome (BWS) observed is a rare, genetically heterogeneous disorder that may be due to a de-novo mutation, or rarely to an autosomal dominant transmission. The gene for BWS is localized on chromosome 11 in the 11p15.5 region, and the characteristic phenotype occurs due to an imbalance of this gene (Jones, 1997
). Since no further molecular cytogenetic investigation could be performed and the parents could not be examined, the disease could not be classified as either de-novo or inherited in this case.
The incidence of minor malformations found in five children (6.8%) is within expected values, though these vary widely in the literature. If the incidence of minor malformations is reviewed in a systematic way, this incidence may range between 4% and 40% in the normal population (Myrianthopoulos and Chung, 1974; Leppig et al., 1987
), and is mainly determined by the methodology applied.
In order to exclude a clinically significant increase in major malformations, a follow-up trial of at least 1000 children would be required, for which data collection is currently underway. Therefore, although the results and conclusions of this initial analysis are limited due to the small number of pregnancies and children, these first data on neonatal outcome and incidence of abnormalities are, in themselves, reassuring since they are within the same range as have been reported for IVFembryo transfer pregnancies in much larger patient subsets.
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Acknowledgements |
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Notes |
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References |
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Submitted on October 23, 2000; accepted on April 4, 2001.