Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report

F. Olivennes1,4, B. Mannaerts2, M. Struijs2, M. Bonduelle3 and P. Devroey3

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Gonadotrophin-releasing hormone (GnRH) antagonists have been proven safe and effective, with no adverse effects on offspring in animal studies. Careful study of pregnancy outcome in humans is mandatory. METHODS AND RESULTS: This preliminary report includes follow-up data of patients treated with the GnRH antagonist, ganirelix, during ovarian stimulation for IVF or ICSI. In total, 333 patients were randomized in a multicentre, double-blind, dose-finding study of ganirelix, at six different doses ranging from 0.0625 to 2 mg. In total, 68 vital intrauterine pregnancies were established that resulted in the birth of 46 singletons, 12 twins and one triplet. Follow-up of the 67 pregnant patients (one subject was lost to follow-up) revealed six miscarriages (9%). Of the 61 subjects with an ongoing pregnancy, two with a singleton pregnancy did not give birth to a live-born infant (one spontaneous abortion in week 19, and one intrauterine death in week 27). The mean gestational age was 39.4 weeks for singleton pregnancies, and 36.6 weeks for multiple pregnancies. In total, 73 infants (33 boys, 40 girls) were born. A birth weight <2500 g was reported for 8.7% and 54.2% of the infants resulting from singleton and twins delivery respectively. One major congenital malformation was diagnosed; a boy with Beckwith–Wiedemann syndrome (exomphalos and macroglossia). Seven minor malformations were reported among five infants. CONCLUSIONS: In this first follow-up study, the incidence of adverse obstetrical and neonatal outcome was comparable with reported incidences for IVF–embryo transfer pregnancies.

Key words: congenital malformations/GnRH antagonist/infertility treatment/ovarian stimulation/perinatal outcome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The prevention of premature LH surges during ovarian stimulation is essential to rule out premature luteinization leading to disrupted oocyte maturation and cycle cancellation. Current care for preventing premature LH surges is treatment with a combination of gonadotrophin-releasing hormone (GnRH) agonist and gonadotrophins. Prospective and retrospective children follow-up studies have been performed previously with IVF and intracytoplasmic sperm injection (ICSI) patients treated with GnRH agonist for ovarian stimulation (MRC, 1990Go; Rufat et al., 1994Go; Bonduelle et al., 1996Go, 1999Go; Wisanto et al., 1996Go; Bergh et al., 1999Go; Loft et al., 1999Go; Out et al., 1999Go; Westergaard et al., 1999Go). The collection of such data is the only tool by which potential adverse health effects of drugs or assisted reproductive treatment procedures to the mother, fetus and/or live-born infant may be monitored. To date, the outcomes of these studies have indicated that pregnancies resulting from such treatment in combination with assisted reproductive treatment are exposed to a higher rate of perinatal adverse outcome, mainly related to a high prevalence of multiple pregnancies (MRC, 1990Go; Rufat et al., 1994Go; Bergh et al., 1999Go; Westergaard et al., 1999Go). In contrast, the incidence of congenital abnormalities is not higher among IVF–embryo transfer pregnancies as compared with data obtained from the general population (Shoham et al., 1991Go).

Although GnRH agonist have been proved to be safe and effective, these compounds have intrinsic disadvantages, including initial flare-ups requiring 2–3 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 pituitary–gonadal 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, 1998Go) of the GnRH antagonist ganirelix (Orgalutran®) were followed during their pregnancy, and the data concerning neonatal outcomes, including congenital malformations, were collected.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients and treatment procedures
In a double-blind, multicentre, randomized dose-finding study (The ganirelix dose finding study group, 1998Go), a total of 333 patients was randomized to one of six dose groups. Each treatment group underwent ovarian stimulation with recombinant FSH (Puregon®, NV Organon, Oss, The Netherlands ), and treatment with ganirelix (Orgalutran®/Antagon®, NV Organon ) was started on day 6 of stimulation. Ganirelix was administered daily in doses of 0.0625, 0.125, 0.25, 0.5, 1.0 or 2.0 mg, up to and including the day of triggering ovulation. Fertilization was obtained either with classical IVF or by using ICSI. A clinical pregnancy was established (heart activity as observed by ultrasound scan 5–6 weeks after embryo transfer) in 68 patients (20.4% per initiated cycle).

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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients
The mean patient age was 31.4 (range 20–38) years. A total of 82% of the patients was primiparous. The total mean (± SD) duration of ganirelix treatment was 5.2 ± 2.1 days.

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 IGo. 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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Table I. Pregnancy and delivery complications
 
Neonatal outcome and infant follow-up
The data on the perinatal outcome are presented in Table IIGo. The mean (± SD) gestational age was 39.4 ± 1.7 weeks and 36.6 ± 2.3 weeks for patients with a singleton and twin pregnancy respectively. A total of 15.3% of the deliveries occurred prematurely, at <37 weeks of amenorrhoea (WA). This rate was 8.7% in the singleton pregnancies, and 33.3% in the twins. Only one pregnancy (1.7%) ended before 32 weeks due to a preterm delivery of a twin.


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Table II. Gestational age and birth weight
 
In total, 73 babies were born originating from one triplet, 12 twins, and 46 singleton pregnancies. Nineteen babies had a birth weight <2500 g, and most of these (n = 15 ) were born from a multiple pregnancy. Two babies (2.7%), both of which originated from twin pregnancies, weighed <1500 g. Overall, 40 girls (54.8%) and 33 boys (45.2%) were born (sex ratio girls/boys: 1.2). No difference was seen between the sex distribution of the singleton or multiple pregnancy group.

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 Beckwith–Wiedemann 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.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This is the first reported follow-up of patients who became pregnant after treatment with recombinant FSH and the new GnRH antagonist, ganirelix (Orgalutran®), to support the safety of this treatment regimen. Reporting the follow-up of pregnancies and babies obtained with new drugs should be a mandatory task in assisted reproduction technologies. Newly developed GnRH antagonists have recently become available for clinical studies, and will be used widely in the near future for the prevention of premature LH surges during ovarian stimulation.

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, 1990Go; Rufat et al., 1994Go; Bergh et al., 1999Go; Loft et al., 1999Go; Westergaard et al., 1999Go).

One major malformation among 73 children (1.4%) is within the expected figure of major malformation (2–4%) in the ICSI and IVF population (Bonduelle et al., 1999Go; Westergaard et al., 1999Go; Wennerholm et al., 2000Go). The Beckwith–Wiedemann 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, 1997Go). 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, 1974Go; Leppig et al., 1987Go), 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 IVF–embryo transfer pregnancies in much larger patient subsets.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This follow-up study was performed by The Ganirelix Dose-finding Study Group, and included the following investigators: T.Åbyholm, P.Devroey, K.Diedrich, D.de Jong, T.Hillensjö, B.Hedon, J.Itskovitz-Eldor, J.Kahn, O.Naether, F.Olivennes, S.Pavlou, B.Tarlatzis and L.Westergaard.


    Notes
 
4 To whom correspondence should be addressed at: Hôpital Antoine Béclère, Service de Gynecologie-Obstétrique 157,Rue de la Porte de Trivaux, 92141 Clamart, France. Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Bonduelle, M. (2001) Neonatal outcome of pregnancies established after treatment with recombinant FSH and ganirelix for ART. Gynecol. Endocrinol., 15 (Suppl. 1) , abstract 13.

Bonduelle M., Wilikens, A., Buysse, A. et al. (1996) Prospective study of 877 children born after intracytoplasmatic sperm injection (ICSI) with ejaculated, epididymal and testicular spermatozoa and after replacement of cryopreserved embryos obtained after ICSI. Hum. Reprod., 11, 131–159.[ISI][Medline]

Bonduelle, M., Camus, M., De Vos, A. et al. (1999) Seven years of intracytoplasmic sperm injection and follow-up of 1987 subsequent children. Hum. Reprod., 14 (Suppl. 1), 243–264.[ISI][Medline]

Jones, K.L. (1997) Early overgrowth with association defects. Chapter E. In Smith's Recognizable Patterns of Human Malformation. W.B.Saunders Co., pp. 164–167.

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Myrianthopoulos, N.C. and Chung, C.S. (1974) Congenital malformations in singletons: epidemiologic survey. Report from the Collaborative Perinatal project. Birth Defects Orig. Artic. Ser., 10, 1–58.

Out, H.J., Mannaerts, B.M.J.L., Driessen, S.G.A.J. and Coelingh Bennink, H.J.T. (1999) A pregnancy and children follow-up study of three randomised clinical trials with recombinant follicle-stimulating hormone (Puregon) in in-vitro fertilisation. Middle East Fert. Soc. J., 4, 28–34.

Rufat, P., Olivennes, F., de Mouzon, J. et al. (1994) Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989). Fertil. Steril., 61, 324–330.[ISI][Medline]

Shoham, Z., Zosmer, A. and Insler, V. (1991) Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer. Fertil. Steril., 55, 1–11.[ISI][Medline]

The Ganirelix Dose-finding Study Group (1998) A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon®). Hum. Reprod., 13, 3023–3031.[Abstract]

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Submitted on October 23, 2000; accepted on April 4, 2001.