Human Reproduction, Vol. 17, No. 7, 1755-1761,
July 2002
© 2002 European Society of Human Reproduction and Embryology
Obstetric outcome among women with unexplained infertility after IVF: a matched case–control study
1 Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki and 2 STAKES, National Research and Development Centre of Welfare and Health, Helsinki, Finland
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Abstract |
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BACKGROUND: Infertility itself and also assisted reproductive treatment increase the incidence of some obstetric complications. Women with unexplained infertility are reported to be at an increased risk of intrauterine growth restriction during pregnancy, but not for other perinatal complications. METHODS: A matched case–control study was performed on care during pregnancy and delivery, obstetric complications and infant perinatal outcomes of 107 women with unexplained infertility, with 118 clinical pregnancies after IVF or ICSI treatment. These resulted in 90 deliveries; of these, 69 were singleton, 20 twin and one triplet. Two control groups were chosen from the Finnish Medical Birth Register, one group for spontaneous pregnancies (including 445 women and 545 children), matched according to maternal age, parity, year of birth, mother's residence and number of children at birth, and the other group for all pregnancies after IVF, ICSI or frozen embryo transfer treatment (FET) during the study period (including 2377 women and 2853 children). RESULTS: Among singletons, no difference was found in the mean birthweight, and the incidence of low birthweight (<2500 g) was comparable with that of the control groups. No differences were found in gestational duration, major congenital malformations or perinatal mortality among the groups studied. Among singletons in the study group, there were more term breech presentations (10.1%) compared with both spontaneously conceiving women and all IVF women (P < 0.01). The rate of pregnancy-induced hypertension was significantly lower among singletons in the study group (P < 0.05) compared with other IVF singletons. The multiple pregnancy rate was 23.3% in the study group. The obstetric outcome of the IVF twins was similar to both control groups. CONCLUSIONS: The overall obstetric outcome among couples with unexplained infertility treated with IVF was good, with similar outcome compared with spontaneous pregnancies and IVF pregnancies generally.
Key words: birthweight/IVF/matched case-control study/obstetric outcome/unexplained infertility
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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A high frequency of multiple births is the main factor that leads to adverse outcome in IVF pregnancies (Bergh et al., 1999
). However, previous reports have shown an increased risk of preterm delivery and fetal growth retardation even in singleton pregnancies (Tan et al., 1992; Gissler et al., 1995a; Verlanen et al., 1995; Tanbo et al., 1995; McElrath and Wise, 1997; Tarlatzis and Grimbizis, 1999; Bergh et al., 1999). Studies have shown that infertility itself contributes to increased obstetric risks (Ghazi et al., 1991) and that subfertility is a predictor for low birthweight (Williams et al., 1991).
Only a few studies have been conducted to evaluate the possible differences in pregnancy complications in different infertility subgroups. Women with unexplained infertility who were treated with assisted reproductive technology had a higher risk of delivering a child with low birthweight compared with couples with other causes of infertility (Wang et al., 1994). One hypothesis could be that the same unknown mechanism that causes subfertility could impair the uterine or placental circulation, resulting in intrauterine growth retardation (IUGR) of the fetus.
The aim of our study was to compare the obstetric and perinatal outcome among women who had unexplained infertility and who delivered after IVF or ICSI treatment with those of matched controls of spontaneous pregnancies and all IVF, ICSI and frozen embryo transfer frozen embryo transfer (FET) pregnancies.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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A total of 118 clinical pregnancies among 107 women with unexplained infertility were achieved after IVF or ICSI treatment at Helsinki University Central Hospital between January 1, 1993 and March 30, 1999. Of these pregnancies, 90 (76.3%) proceeded to delivery, the remaining 28 (23.7%) resulted in spontaneous abortion. Twenty pairs of twins and one triplet pregnancy occurred. The sole triplet pregnancy resulted from a two-embryo transfer. The triplets were born healthy at 33 weeks gestation, but were excluded from the analyses because there were insufficient matching controls for them in the Finnish Medical Birth Register (MBR). Thus, after excluding the triplet pregnancy and those pregnancies ending in spontaneous abortion, the study group refers to the data of 86 women with 89 deliveries and 109 infants. Only the pregnancies ending in birth were included in the analyses.
A delivery was defined as a live birth or a stillbirth after 22 weeks gestation or a birthweight >500 g. Small for gestational age (SGA) was defined as birthweight at the gestational age <–2 SD of the Finnish Population mean according to sex (Pihkala et al., 1989). A major congenital anomaly is defined as a significant congenital structural anomaly, chromosomal defect or congenital hypothyroidism involved in a birth with congenital anomalies. This does not include hereditary diseases and other diseases not associated with congenital anomalies, dysfunction of organs or tissues, developmental disabilities, congenital infections, isolated minor dysmorphic features, normal variations and common less significant congenital anomalies, which are included in the exclusion list utilized by the Malformation Register (STAKES, 2001). Pregnancy-induced hypertension (PIH) was defined as a blood pressure of 
140/90 mmHg (after 20 weeks gestation), or an increase in systolic blood pressure of 30 mmHg or an increase in diastolic blood pressure of 15 mmHg (Gifford et al., 1990). A smoker was defined as a woman who smoked at least during the first trimester of pregnancy.
The intensity of use of antenatal care was measured by a gestational age-adjusted national recommendation, given by the Ministry of Health and Social Affairs (Gissler et al., 1995a), where level 1 means that women had fewer visits than recommended; level 2 means that women had 0–69% more visits than recommended and level 3 means that women had over 70% more visits than recommended.
The infertility was defined as unexplained, if the comprehensive infertility evaluation failed to reveal any apparent cause (Isaksson and Tiitinen, 1998). The mean age (± SD) of the women in the whole study group at the time of conception was 33.8 ± 3.2 years (range 20–40) and the mean duration of infertility was 6.2 ± 2.9 years (range 1.5–15). The infertility was primary for 67 (56.8%) and secondary for 51 (43.2%) of the treatment cycles. Earlier, the women had had a mean of 0.6 ± 0.8 (range 0–3) IVF treatment cycles. A clinical pregnancy was defined as a pregnancy showing a visible gestational sac in transvaginal ultrasound examination 5 weeks after embryo transfer.
The standardized ovarian stimulation protocol for IVF treatment was used in all IVF and ICSI cycles: pituitary down-regulation with a GnRH analogue, followed by daily injections of gonadotrophins. Oocyte retrieval was performed, 36–38 h after administration of HCG, by ultrasound-guided transvaginal aspiration (Isaksson et al., 2000). A mean of 12.0 ± 6.0 (range 1–37) oocytes per cycle was obtained. This in turn yielded a mean of 6.4 ± 4.2 (range 1–20) normally fertilized and cleaved embryos. Embryo transfer was performed 2 days after follicle aspiration. The number of embryos transferred was one in 15 cycles (12.7%), two in 97 cycles (82.2%) and three in six cycles (5.1%). The luteal phase was supplemented with vaginally administered progesterone. In 10 treatment cycles (among eight patients), ICSI was performed for the following reasons: for six of the couples no fertilization had occurred in an earlier IVF attempt; for one couple the fertilization percentage had been exceptionally low in an earlier attempt; and in one male, the sperm motility was exeptionally low on the day of ovum retrieval.
The MBR was used to obtain information on all pregnancies and deliveries. The diagnoses of malformations were verified from the Finnish Malformation Register. The MBR is a statutory nationwide register, which includes information on maternal background, pregnancy, delivery and perinatal outcome. The data quality of MBR has been shown to be high in previous studies (Gissler et al., 1995b).
Two different control groups were chosen from the MBR. One group included women with non-assisted pregnancy and delivery (n = 445 for women and n = 545 for children, i.e. 5xnumber of deliveries among cases; later called control group I). These controls were matched according to maternal age, parity, year of delivery, mother's residence (Southern Finland) and number of children at birth. The other group included all women delivering singletons or twins after IVF, including ICSI or FET treatment in southern Finland during the study period (n = 2377 for women and n = 2853 for children; control group II). Since no information on duration or aetiology of infertility is available in the MBR, all deliveries after IVF, ICSI and FET were included in this group.
The factors studied were maternal background, the total number of antenatal visits, intensity of use of antenatal care, gestational age at birth, birthweight, pregnancy and delivery complications, mother's hospitalization, mode of delivery, infant's outcome, major congenital anomalies and the need for intensive care.
The study was approved by the Institutional Review Board of Helsinki University Central Hospital and the record linkage was approved by the national data protection authorities.
Comparisons between groups and statistical analysis were performed using the SAS computer program, and t-test, Fisher's exact test, test for proportions and 
2-test, also adjusted by the Bonferroni method. Statistical significance was defined as P < 0.05.
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Results |
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Table I
shows the background characteristics and matching criteria of women with unexplained infertility who delivered after IVF treatment (study group), women conceiving spontaneously without infertility (control-group I), and all women delivering after IVF treatment (control-group II). A higher proportion of the women in the study group were married or cohabiting (96.6%; P < 0.01) than in the spontaneously conceiving group (87.0%). In contrast, a lower proportion (5.6%; P < 0.05) of the study group were smokers compared with the spontaneously conceiving group (13.3%). Background characteristics of the study group did not differ from the total IVF group.
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Table II
shows the use of antenatal care and hospital care in the three groups. There were significantly more visits to the hospital outpatient clinic among women with singletons in the study group compared with women conceiving spontaneously (P < 0.001). Among women with twins in the study group there were significantly more visits to the hospital outpatient clinic compared with both control groups I and II (P < 0.05). The total number of antenatal visits includes all visits in the primary care and all visits to the hospital outpatient clinic. The rate of hospital care was lower among women with singletons in the study group (18.8%) compared with singletons in the control group II (37.1%; P < 0.01). When measuring the intensity of use of antenatal care by gestational age-adjusted national recommendations, given by the Ministry of Health and Social Affairs (Gissler et al., 1995a), the intensity of antenatal care was high in the study group, particularly for twin pregnancies, and it reached statistical significance (P < 0.05) for twins when compared with spontaneously conceived twins.
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Prenatal karyotyping was performed in 10.1% of singleton and 2.5% of twin pregnancies in the study group, and no difference was observed when comparing these rates with the corresponding rates for controls.
None of the women with singletons in the study group had PIH and the rate of PIH was significantly (P < 0.05) lower than among all IVF singletons (Table III).
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Among singletons in the study group, there were many more term breech presentations (10.1%) compared with both spontaneously conceiving women (P < 0.01) and all IVF women (P < 0.01; Table IV
). The rate of epidural analgesia was higher among women in the study group carrying twins compared with all IVF women carrying twins (P < 0.05). No differences in the mean gestational duration or the rate of Caesarean sections were found between the groups studied.
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No differences were found when comparing the mean birthweight and the mean gestational duration among singletons and twins in the three groups (Table V
). Also the rates of low and very low birthweight infants were comparable. No difference was observed when comparing the 1 min Apgar scores and umbilical artery pH between the three groups studied. However, the rate of asphyxia, a clinical diagnosis as determined by the paediatrician examining the newborn, was significantly (P < 0.05) higher among the singletons in the study group compared with spontaneously conceived babies. This difference became insignificant after taking account of the Bonferroni adjustment. No difference was found in the rate of perinatal mortality or major congenital anomalies between the groups (Table VI).
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Five major congenital anomalies were detected among singletons in the study group (7.2%) and one among the twins (2.5%). Among the singletons, these were: bilateral pes equinovarus, unilateral pes equinovarus, congenital hydronephrosis, ventricular septum defect and postaxial polydactyly. Furthermore, one newborn twin was found to have asymmetry of left lower face and ear. No chromosomal defects were found among the newborn in the study group after IVF or ICSI treatment.
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Discussion |
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In the present study, the overall obstetric and neonatal outcome in IVF pregnancies was good. Our study shows that by carefully choosing age- and parity-matched controls, the elevated rate of preterm deliveries, found in other studies (Rizk et al., 1991
; Tan et al., 1992; Olivennes et al., 1993) disappeared. Moreover, the perinatal outcome in women with unexplained infertility did not differ from other infertile couples.
The selection of control groups is of great importance. In a recent study (Koudstaal et al., 2000a), besides matching for age and parity, couples were also matched for weight, height, medical and obstetric history, date and place of delivery, ethnic origin and smoking habits. Our controls were matched according to age, parity, number of children at birth and area of residence, chosen from a population-based register, with controls delivering the same year as women in the study group. Unfortunately, the MBR does not collect information on women's weight, height or ethnic origin, so these factors could not be compared in our study. In general, no differences in weight have been reported between fertile and infertile women, and probably this is also true for women/couples with unexplained infertility. In our study, the ethnic origin of the women was 97% Finns, so this was not a confounding factor in our results. However, there were small differences in smoking habits and marital status of the study group compared with the spontaneously conceived pregnancies in our study, which reflects differences in social and cultural factors.
One reason for conducting this study was that women with unexplained infertility have been shown to be at an elevated risk of IUGR (Wang et al., 1994). In our earlier study, women with unexplained infertility, who conceived as the result of assisted reproductive technology, delivered babies with a significantly lower birthweight compared with their spontaneous pregnancies (Isaksson and Tiitinen, 1998). Earlier reports do not provide data as to whether the assisted reproductive technology treatment or the infertility itself contributes to the placental insufficiency and IUGR of the fetus (Oliviennes et al., 1993; Wang et al., 1994; Isaksson and Tiitinen, 1998). To our knowledge, although the size of the study population was limited, this is the first report on obstetric outcome of IVF pregnancies comparing women with unexplained infertility to all infertility subgroups and to appropriately matched controls. Earlier studies have only included unselected material, with all infertility subgroups.
Earlier studies have shown an increased incidence of very low birthweight (<1500 g) among singletons after assisted reproductive technology (Rizk et al., 1991; Tan et al., 1992; McFaul et al., 1993; Olivennes et al., 1993). However, in our study the rate of very low birthweight infants was not elevated. It has been suggested that the elevated rate of very low birthweight infants in earlier studies could be due to the elevated rate of preterm births as well as iatrogenic preterm Caesarean sections (Reubinoff et al., 1997), but our study does not support the earlier findings. On the contrary, in our study the rate of low birthweight (<2500 g) babies was comparable with the control groups and even lower (2.9%) compared with 11.5–13.8% for all subgroups reported in other studies (Tanbo et al., 1995; Koudstaal et al., 2000a). The 1 min Apgar scores and the umbilical artery pH were comparable in the groups studied. Even though statistically ambiguous, there was an elevated rate of asphyxia, a clinical diagnosis determined by the paediatrician (P < 0.05), without Bonferroni adjustment in singletons in the study group, including five singletons with mild asphyxia, all infants having an umbilical artery pH >7.12. Premature birth did not explain these findings, because all these babies were delivered fullterm. The perinatal mortality was, however, low both among singletons (1.5%) and twins (0%).
The rate of multiple births (23.3%) was comparable with earlier IVF reports from Finland (Gissler and Tiitinen, 2001) and Europe (Nygren and Nyboe Andersen, 2001). In our study, IVF twin pregnancies had a similar obstetric and perinatal outcome as spontaneous twin pregnancies. However, we had only 20 twins in the unexplained infertility study group, which limits comparisons with the control groups. A recent study supports our findings, by showing that the rate of prematurity and birthweight of IVF twins were comparable to spontaneously conceived twins (Westergaard et al., 1999). In another study (Koudstaal et al., 2000b), IVF twins had a different outcome in comparison with spontaneously conceived twins. The mean gestational age was shorter (not significant) and the average birthweight lower (P = 0.04), the incidence of discordant birthweight was higher and vaginal bleeding more frequent among IVF pregnancies compared with spontaneously conceived twins. Unfortunately, we could not use zygosity as a matching criterion. This might have explained the better outcome in our IVF data compared with other studies. Monozygotic twins are known to carry increased risks for preterm delivery, discordance in birthweight and low birthweight. Multiple pregnancies constitute the most serious complication for both mother and children after assisted reproductive technology. This can be avoided with elective single embryo transfer and good cryopreservation programmes (Tiitinen et al., 2001).
The total number of antenatal visits in the three groups studied was equal, but there were significantly more visits to the hospital outpatient clinic among women in the study group. It is difficult to estimate the role of the elevated rate of these visits for reducing obstetric complications in the study group, because this was not the issue of this study.
Whereas some recent studies have found an increased rate of some congenital anomalies such as neural tube defects, alimentary atresia, omphalocele and hypospadias among newborn infants conceived by IVF (Bergh et al., 1999; Ericson and Källén, 2001), these were not apparent in our study, confirming another recent study (Westergaard et al., 1999). All cases in our study were separately checked from the Finnish Birth Register and Malformation Register, and only the major congenital anomalies were included. However, the increased risk of congenital anomalies in these large studies can partly be explained by the characteristics of women undergoing IVF, e.g. age, parity, multiple pregnancy and period of involuntary childlessness (Westergaard et al., 1999; Ericson and Källén, 2001). Some authors have also suggested an increased risk of congenital anomalies after ICSI (Kurinzuk and Bower, 1997), but we found no congenital anomalies in the study group among children born after ICSI. The rate of congenital anomalies was not elevated in a recent study, which reported a congenital anomaly rate of 1.7% after ICSI (Westergaard et al., 1999).
In our study, the rate of spontanous abortions was 23.7%, which concords with earlier studies reporting rates of 20–25% after IVF. The risk of spontaneous abortion in women who conceive after fertility therapy appears to be similar to that of infertile women who conceive without treatment (Pezeshki et al., 2000). In addition, there was no association between the aetiology of infertility and the occurrence of spontaneous abortion.
No differences were found when comparing IVF and ICSI pregnancies in women with unexplained infertility to all aetiologies. Since no information on the aetiology of infertility is available in the MBR, we could not include women with unexplained infertility treated in other clinics in the analyses. To verify our findings, a comparison should be made in a larger population between unexplained versus other subgroups. However, this is not possible with the current Finnish databases without ad-hoc data collection (Gissler and Tiitinen, 2001).
In conclusion, the obstetric and perinatal outcome after IVF treatment among couples with unexplained infertility is good, and comparable with spontaneous pregnancies.
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Acknowledgements |
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We are grateful to Dr Annukka Ritvanen for collecting data from the Finnish Malformation Register and helping in interprinting the data on malformations. The study was supported by grants from Helsinki University Central Hospital Research Funds, Finska Läkaresällskapet (Medical Society of Finland) and the Paulo Foundation for Medical Research, Helsinki, Finland.
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3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, P.O.Box 140, FIN-00029 HUS, Finland. E-mail: rita.isaksson{at}hus.fi
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Submitted on August 13, 2001; resubmitted on January 25, 2002; accepted on March 7, 2002.
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