1 Infertility Centre, University Hospital Gent, Belgium
2 To whom correspondence should be addressed at University Hospital, De Pintelaan 185, B-9000 Gent, Belgium. Email: petra.desutter{at}ugent.be
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Abstract |
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Key words: intra-uterine insemination/IVF/perinatal outcome/pregnancy
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Introduction |
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One of the main reasons for the increased risk of ART pregnancies is the high rate of multiple pregnancies after ART (Craft and Al Shawaf, 1991; Tanbo et al., 1995
; Bernasko et al., 1997
; Bergh et al., 1999
; Draper et al., 1999
; ESHRE Capri Workshop Group, 2000
; Ozturk et al., 2001
; Adamson and Baker, 2004
) but, even after correction for this confounder, the outcome remains of poorer quality (Wang et al., 1994
, Wang et al., 2002
; Tanbo et al., 1995
; Bergh et al., 1999
; Dhont et al., 1999
; Tarlatzis and Grimbizis, 1999
; Shieve et al., 2002
; Jackson et al., 2004
). An important question is whether this is to be attributed to the characteristics of the patients (maternal age, parity, duration of infertility, etc.) or to the ART procedures themselves. Indeed, Wang et al. (2002)
have reported a 50% higher prematurity rate after intra-uterine insemination (IUI) as well as after other forms of ART. Also in a recent retrospective study comparing IUI pregnancies with spontaneous conceptions (Gaudoin et al., 2003
), patients treated with IUI were at increased risk for preterm birth and low birth weight infants. On the other hand, Nuojua-Huttunen et al. (1999)
have shown that IUI in itself does not lead to any increase in perinatal risk, except when hormonal stimulation is used, resulting in multiple pregnancies. Specific characteristics of an infertility population, such as higher maternal age and lower parity, are well known obstetric risk factors, so that it could a priori be expected that pregnancy outcome is poor in this group, whatever the method of treatment used to obtain a pregnancy (Craft and Al Shawaf, 1991
; Gissler et al., 1995
; Verlaenen et al., 1995
; Dhont et al., 1999
; Westergaard et al., 1999
; Olivennes et al., 2002
; Wang et al., 2002
). Some studies suggest that the infertility in itself could increase the risks for low birth weight and preterm birth (Craft and Al Shawaf, 1991
; Draper et al., 1999
; Olivennes et al., 2002
; Wang et al., 2002
), although not all authors agree on this (Tanbo et al., 1995
). In a recent literature review (Lambert, 2003
), it is also strongly suggested that indeed the infertility itself is to be held responsible for the worse perinatal outcome, both after IVF and after IUI.
The present study is a matched casecontrol study which aims to compare two ART methods, namely IVF and IUI, as treatment methods in an infertile population. The purpose of this study is to analyse whether IVF has an intrinsically higher perinatal risk than IUI in this matched patient population, so that confounding factors, such as life-style and infertility-related issues, are eliminated, and possible differences are not to be attributed to patient characteristics, but to the technique itself.
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Materials and methods |
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IVF
Only patients who were treated with IVF for mild male or unexplained infertility or endometriosis were analysed. No severe male infertility cases undergoing ICSI were included in the present study. All patients underwent controlled ovarian stimulation after cycle synchronization with a standard contraceptive pill for 26 weeks. In >90% of our patients, a short GnRH agonist protocol was used, consisting of 0.1 mg of triptorelin (Decapeptyl, Ipsen, France), injected s.c. from day 5 onwards after discontinuation of the oral contraceptive. This was followed by HMG (either Humegon, Organon, The Netherlands or Menopur, Ferring, Germany) or recombinant FSH (either Gonal-F, Serono, Switzerland or Puregon, Organon, The Netherlands) from day 5 onwards. The starting dose in a first cycle was always 225 IU, but this dose was adjusted after 7 days, according to the individual response of the patient. The follicular phase was monitored by means of transvaginal ultrasound scanning of the ovaries and serum estradiol measurements (the latter especially in poor responders and in patients at risk for the ovarian hyperstimulation syndrome).
In 10% of our patients, a long GnRH agonist protocol was used. Triptorelin (Decapeptyl, Ipsen, France) 3.75 mg i.m. was administered when the patient had been taking her contraceptive pill for at least 2 weeks. Another 2 weeks after triptorelin administration she could stop the pill and start 1 week later with the gonadotrophin injections. Monitoring was similar to the monitoring in patients treated with the short protocol.
HCG (Pregnyl, Organon, The Netherlands) 5000 or 10 000 IU was administered when half of all mature follicles had reached a mean diameter of at least 20 mm, measured in two planes. At 34 h after HCG injection, oocytes were retrieved by transvaginal ultrasound-guided follicular puncture under general anaesthesia using propofol. IVF was performed as described elsewhere (Laverge et al., 2001). No major changes in techniques or culture conditions were introduced during the study period.
In 1997 we started transferring one embryo in good prognosis cases, especially in patients of <37 years old, in first or second treatment cycles and when at least one excellent or good quality embryo was present (De Sutter et al., 2003). In other cases, two embryos were transferred.
The luteal phase was supported by either progesterone i.m. injections 50 mg daily or intravaginally 3 x 200 mg (Utrogestan, Piette Laboratories, Belgium), or three injections of 1500 IU of HCG (Pregnyl, Organon, The Netherlands).
Pregnancy detection
Pregnancy was diagnosed by the detection of a positive serum HCG at least 14 days after insemination or embryo transfer, followed by a rise in HCG levels. All patients received a transvaginal ultrasound scan between 6 and 7 weeks to differentiate between biochemical and clinical (presence of an intra-uterine fetal sac) pregnancies and to diagnose ectopic implantations. All pregnancies were monitored further by transvaginal ultrasound until 12 weeks amenorrhoea. Both singleton and twin pregnancies were included. Pregnancy duration was calculated exactly from the date of insemination or of oocyte retrieval.
Pregnancy outcome parameters
Primary pregnancy outcome parameters recorded were duration of pregnancy, birth weight, perinatal mortality, presentation of the child and Caesarean section rates. Secondary outcome measures were incidence of preterm contractions, stay in a neonatological intensive care unit, Apgar score, incidence of blood loss in the first, second and third trimester, and maternal hypertension. A preterm delivery was defined as a delivery at a pregnancy duration of <37 completed weeks, and low birth weight as <2500 g. Perinatal mortality rates included stillbirths with a birth weight of 500 g and neonatal deaths during the first postnatal week.
Patient selection and matching
Since our IVF database is larger and more complete than the IUI database, we started by selecting all patients having become pregnant after IUI and treated between January 1997 and December 2001. In total, 413 patients were retrieved from the IUI database and, in order to gather the necessary detailed data for the present study, 385 questionnaires were sent to couples for whom the address was available. We received 182 replies and could include 166 patients in the study. Sixteen questionnaires were incomplete and therefore rejected. For these 166 patients, a match was searched for in the IVF database on the basis of the following criteria: maternal age identical±2 years, parity and plurality identical, and date of delivery identical±31 days for singletons and±365 days for twins. Matching was not done for fetal sex, because it was not possible to find an appropriate control for each case. Fetal sex rates did, however, not differ between both groups. Each match was unique and for 40 cases no control could be found so that the final study was performed on 126 pairs of patients, 112 singletons and 14 twins each after IVF and after IUI.
Statistics
Because none of the analysed parameters were normally distributed, non-parametric tests were used, namely the Wilcoxon paired test for continuous parameters and the Mc Nemar paired test for categorical variables. Apgar scores were compared using Fisher's exact test, using a cut-off level of 7. Because of the matched casecontrol design, sample size was sufficient to reach enough power to compare the primary outcome parameters, anticipating the same percentage of premature births after IUI as in the general population and estimating a 3-fold increase after IVF. The level of statistical significance was set at P=0.05. For the analysis, S-PLUS® 6.1 for Windows was used.
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Results |
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In the casecontrol analysis, maternal age, parity and plurality were similar in both groups because of the matching procedure [30.3±3.6 years in the IUI group versus 29.3±4.3 in the IVF group (NS); 91 primiparous and 31 secundiparous women in each group; 112 singletons and 14 twins in each group]. Fetal sex was not matched for, and in the IUI group 55.6% of all children were boys, compared with 43.7% in the IVF group (P=0.115). Congenital anomalies and perinatal deaths were rare events so that no statistical comparison was made (there was one perinatal death in the IUI and two in the IVF group, and four congenital anomalies in the IUI and two in the IVF group, both NS).
Comparisons for primary and secondary outcome measures are shown in Table I. None of the studied parameters was significantly different between groups. Twenty out of 126 babies born after IUI had a low birth weight (15.9%), with two children <1500 g. Of the singletons, only 9.8% weighted <2500 g. In the IVF group, 17 babies had a low birth weight (13.5%; 9.3% of singletons) and one child weighed <1500 g. These differences are not statistically significant.
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Discussion |
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It is clear that the global poorer obstetric and perinatal outcome in our study is mostly due to the included twin pregnancies. According to the SPE (2002), only 1.98% of all deliveries in the overall population in our country were twin deliveries, whereas in our data set this rate was 25% for IVF and 9% for IUI. In our matched analysis, it was 9.5%, which is our exact twinning rate after IUI. If the real twinning rate after IVF had been used for the analysis, the outcome after IVF would obviously have been even worse. The matching procedure did not allow comparison of the real multiple pregnancy rates after both methods of treatment. Anyway, the high rate of multiple pregnancies obviously explains much of the worse outcome after ART as compared with spontaneous conceptions. Fortunately, since 2003, the number of embryos to be transferred in IVF in Belgium has been restricted by law (Royal Decree, 2003
), and the multiple pregnancy rate after IVF is expected to decrease in the coming years. Iatrogenic multiple pregnancies will, however, continue to occur as long as no efforts are made to set the correct indications for the use of controlled ovarian stimulation in non-IVF treatment (Kaplan et al., 2002
).
The present study did not analyse miscarriage and ectopic pregnancy rates after IUI and IVF, because the groups were matched on date of delivery, and therefore only ongoing pregnancies were included. Blood loss in the first trimester, however, was analysed and, similarly to Pezehski et al. (2000), we also found a higher incidences than in the general population, even after IUI. After IVF, it has been suggested that an abnormal implantation process or subclinical vanishing twins could explain the increased incidence of bleeding during the first trimester, but it is not clear why this would be the case after IUI.
Our data contradict the conclusions of Wang et al. (2002), who detected differences in incidence of preterm birth after different methods of infertility treatment. However, that study was not a matched casecontrol study, and other confounding factors influencing prematurity may not have been accounted for. The comparison of two methods of treatment in the same patient population is the only way to detect possible intrinsic risks of the procedures themselves. One can expect that matching of the groups eliminates not only possible bias due to age, parity and plurality, but also that due to numerous other possible confounders which are hard to study. Our database does not include registration of life-style factors, such as smoking or alcohol consumption, dietary habits, education and professional activities, and other factors which are known to influence obstetric and neonatal outcome. Since in our programme couples with mild male or unexplained infertility and mild endometriosis are always treated first with IUI before IVF is started, there is a more than reasonable chance that these immeasurable confounders are not different between our IUI and IVF groups.
The present study is the second to compare obstetric and perinatal outcome in a matched casecontrol setting between IUI and IVF. As in the study of Nuojua-Huttunen et al. (1999), our data indicate that there are no differences between both groups. If anything, the IVF group even performs better than the IUI group. This finding strongly supports the notion that if pregnancy outcome after ART is worse than after spontaneous conception, this is due to the specific characteristics of the population, and not to the methods of treatment themselves. Of course, it could be that both IUI and IVF hold specific risks in themselves. There are many hypotheses which have tried to explain the worse outcome after IVF and, theoretically, even IUI may offer increased risks because of the in vitro sperm preparation and the insemination act, but this is not very probable. From our study, it seems that not only IVF but also IUI pregnancies thus perform less well than spontaneous pregnancies and this should be a reason for national registries of IUI, careful follow-up of the pregnancies and larger studies to analyse the obstetric and neonatal outcome after IUI.
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Submitted on November 4, 2004; resubmitted on January 1, 2005; accepted on January 24, 2005.