Hum. Reprod. Advance Access originally published online on January 31, 2006
Human Reproduction 2006 21(6):1508-1513; doi:10.1093/humrep/dei503
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Obstetric and perinatal outcome and preliminary results of development of children born after in vitro maturation of oocytes
1 The Family Federation of Finland, Infertility Clinic, 2 The Mannerheim League for Child Welfare, The Foundation for Rehabilitation of Children and Young People and 3 Barnavårdsföreningen i Finland r.f./ADHD-centre, Stenbäckinkatu, Helsinki, Finland
4 To whom correspondence should be addressed at: The Family Federation of Finland, Infertility Clinic, PO Box 849, 00101 Helsinki, Finland. E-mail: viveca.soderstrom-anttila{at}vaestoliitto.fi
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Abstract |
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BACKGROUND: Careful follow-up of children born after in vitro maturation (IVM) of human oocytes is essential because the technique is still very new. METHODS: Obstetric and perinatal data were collected from all deliveries after IVM treatment during 1999–2004. The growth and development of IVM children was assessed at 6, 12 and 24 months using Muenchener Funktionelle Entwicklungs Diagnostik and Bayley Scales of Infants. RESULTS: In total, 43 women [age 31.2 ± 3.9 (mean ± SD) years] gave birth to 40 singleton infants and three sets of twins (multiple rate 7.0%). Obstetric complications occurred in 15 pregnancies (35%). The mean birthweight of singleton infants was 3550 ± 441 g and that of twins 2622 ± 194 g. The rate of preterm birth infants was 5% in singletons. No perinatal deaths occurred. At the age of 12 months, eight children (19%) expressed minor developmental problems and one girl was found to have optical glioma. At 2 years of age, neuropsychological development was within the normal range. CONCLUSIONS: The obstetric and perinatal outcome was good, and the mean birthweight of the infants was normal. Minor developmental delay was overexpressed at 12 months, but the development of the children was normal at 2 years.
Key words: birthweight/follow-up of children/IVM/obstetric/perinatal
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Introduction |
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The first report of childbirth after in vitro maturation (IVM) of immature human oocytes was published in 1991 (Cha et al., 1991
). Immature oocytes were retrieved from unstimulated ovaries during Caesarean section (CS). A few years later, IVM treatments were successfully carried out using transvaginal immature oocyte collection (IOC) (Trounson et al., 1994; Barnes et al., 1995; Russell et al., 1997). During the last few years, IOC and IVM have become a promising treatment in the range of assisted reproductive techniques (ART), with pregnancy rates of 22–35% per embryo transfer (Chian et al., 2000; Lin et al., 2003; Cha et al., 2005; Le Du et al., 2005; Söderström-Anttila et al., 2005). IVM has mostly been offered to patients with polycystic ovaries (PCOs) and also to couples with tubal, male or unexplained infertility (Söderström-Anttila et al., 2005). The advantages of IVM compared with conventional IVF include simple protocols, reduction in costs and avoidance of ovarian hyperstimulation syndrome. Two years ago, it was estimated that approximately 300 infants had already been born from IVM (Chian, 2004). Currently, this number is likely to be much higher.
Thus far, there are only few reports on obstetric and perinatal outcome of IVM pregnancies. Recently, Mikkelsen (2005) reported the outcome of 47 IVM children, including one case of stillbirth. The mean birthweight of the singletons (n = 45) was 3720 g, with very few complications during pregnancy. Another recent study of 24 IVM deliveries showed that gestational age, birthweight and obstetric complications were within the expected range (Cha et al., 2005). Some concern has been voiced regarding the safety of this new method with respect to the health of the children (Cha et al., 2005). To the best of our knowledge, there is thus far no follow-up data available on the growth and development of the IVM children.
At the Infertility Clinic of the Family Federation of Finland, Helsinki, IVM has been carried out in a clinical setting since 1999. Recently, we published the results of 275 cycles, most (87%) of which were carried out in natural cycles without any hormonal pretreatment before IOC (Söderström-Anttila et al., 2005). Insemination (IVM–IVF) and ICSI according to sperm quality resulted in similar pregnancy rates per oocyte retrieval (Söderström-Anttila et al., 2005). During 1999–2004, fresh and frozen–thawed embryo transfers resulted in the birth of 46 infants. The aim of this study was to evaluate the obstetric and perinatal outcome of these first IVM pregnancies in Finland and report the results of neurological and neuropsychological examinations of the IVM children up to the age of 2 years.
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Subjects and methods |
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IVM patients
During 1999–2004, 218 women underwent 275 fresh IVM cycles, resulting in 55 clinical pregnancies and 40 deliveries (37 singletons and three sets of twins). Two women gave birth to singleton infants after a transfer of frozen–thawed IVM embryos (Söderström-Anttila et al., 2005
). One child included in this study was excluded from our previous report comparing IVM–IVF and IVM–ICSI because in this case half of the oocytes were inseminated and the other half were microinjected. The mean ± SD age of the 43 parturients was 31.2 ± 3.9 years (range 24–39 years), and the duration of infertility was 43.9 ± 29.7 months. Two of the mothers delivered twice. The indications for ART were as follows: tubal-only 4, other female-only 10, male factor 10, unexplained 6 and multiple causes 13. Nine women had PCO ovaries and 34 had regular cycles with normal ovaries. Of all parturients, 33 (76.7%) were primiparae and 29 (67.4%) went through their first IVM treatment. Eight couples had previously undergone conventional IVF or ICSI treatments. One mother suffered from Crohn’s disease and rheumatoid spondylitis. She used daily sulphasalazine medication during the pregnancy. Another woman had been operated on because of a cardiac septal defect. All others were healthy. Two of the patients were smokers.
Endometrial priming and hormonal support
The priming of endometrium has been described previously (Söderström-Anttila et al., 2005). Briefly, the patients used oral 17
-estradiol valerate 6 mg daily (Progynova, Schering, Finland) immediately after IOC and vaginal micronized progesterone 600 mg daily (Lugesteron, Leiras, Finland) from the day after IOC. The hormonal support was continued until 9 weeks of gestation, with decreasing dosages over the last 2 weeks. Transvaginal ultrasound examination was performed approximately 5 weeks after embryo transfer to confirm gestation sac or fetal heartbeat.
Pregnancy follow-up
After verification of an intrauterine ongoing pregnancy, the perinatal follow-up was done by an obstetrician at the Family Federation of Finland. Fetal ultrasound examination including measurement of fetal nuchal translucency (NT) thickness was performed between 12 and 13 weeks of gestation. All patients were offered screening for chromosomal abnormalities using a combination of NT measurement with the maternal serum markers free -HCG and pregnancy-associated plasma protein-A. The patients were also offered prenatal diagnosis by chorionic villus sampling or amniocentesis. Routine pregnancy follow-up visits and ultrasound examinations were carried out four to six times during each pregnancy. When applicable, the patients were referred to a tertiary obstetric unit for further follow-up. Mild pre-eclampsia was defined as repeated blood pressure levels 
140/90 mmHg, with proteinuria 0.5 g/day after 20 weeks of gestation. Severe pre-eclampsia was defined as repeated blood pressure levels 160/110 mmHg, with proteinuria 3 g/day after 20 weeks of gestation.
Data collection
Data concerning the course of pregnancy, mode of delivery and the neonatal outcome were collected from the patient records at the Family Federation of Finland and the delivery hospitals. Information on the growth (height and weight) of the children was received from their health information cards and personal growth charts.
Follow-up of growth and development of the children
The growth of the children was assessed at the age of 1 and 2 years. The heights are presented as SD from Finnish standards. The height-related weights are presented as percentiles of Finnish mean values (Sorva et al., 1984).
At the age of 6 and 12 months, the children were physically examined by an experienced paediatric neurologist, and their development was assessed using the Muenchener Funktionelle Entwicklungs Diagnostik (MFED). The method included the examination of the infants in prone, supine and standing positions and the developmental age in crawling, sitting, standing, walking and reaching as well as the assessment of visual and auditory reactions and vocalization and social skills. By using the MFED method, normal development was considered as that seen in 90% of Finnish children in all the other developmental fields except in independent walking at the age of 12 months, when 57% of the healthy Finnish children meet this criteria (Hellbruegge et al., 1978; Autti-Rämö and Granström, 1991; Salokorpi et al., 1998, 2001). A delay of at least 1 month in one to three categories at 6 months and in one to four categories at 12 months was considered a mild developmental delay (MDD). A delay in up to six categories was diagnosed as considerable developmental delay (CDD). A delay in seven fields was considered as severe developmental disorder (SDD). The development of the children at 6 and 12 months was compared to well-documented Finnish national standards (Autti-Rämö and Granström, 1991).
At 2 years of age (24 months ± 4 weeks), the development of the children was assessed according to the Bayley Scales of Infants (Bayley, 1993). The outcome was considered adequate for age if the child reached a mental developmental index (MDI) >85 and MDD was considered if the MDI was 70–85. Mental retardation was defined with MDI values <70. The results were compared to the general population of Finnish children (Tommiska et al., 2003).
Statistical analysis
The relationships between development variables at the age of 1 and 2 years and risk factor variables were analysed by multilinear regression using the SAS software package.
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Results |
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In total, 43 women gave birth to 40 singleton infants and three sets of twins (multiple rate 7.0%). Of all singletons after fresh embryo transfer, 19 were the result of replacement of IVM–IVF and 19 of IVM–ICSI embryos. Two twin gestations started after IVM–IVF and one twin pregnancy after IVM–ICSI embryo transfer. In addition, two cases with vanishing twins occurred. One woman with both intrauterine and tubal pregnancy underwent salpingectomy at 8 weeks of gestation and the intrauterine pregnancy continued uneventfully.
Obstetric outcome
Fourteen women (32.6%) had a prenatal chromosomal screen test using measurements of NT and maternal serum biochemical markers. One sample was screen-positive, but the couple decided not to undergo amniocentesis. In the whole study group, one chorionic villus biopsy and three amniocentesis samples were carried out. One child was found to have a balanced translocation between chromosomes 1 and 8, the same translocation also found in the mother. All other karyotypes analysed were normal.
Thirteen mothers (30.2%) had first-trimester bleeding and three (7.0%) had pregnancy-induced nausea, requiring sick leave or hospitalization. In total, adverse events occurred in 15 pregnancies (35%) during the second and third trimester (Table I). The mean ± SD duration of pregnancy was 282 ± 11 days in singleton (n = 40) and 257 ± 15 in twin pregnancies (n = 3). Four pregnancies ended in a preterm delivery between 249 and 252 days of gestation.
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Delivery was carried out by CS in 34.9% of the patients (Table I). The indications for CS were threatening asphyxia 6, abnormal presentation 3, prolonged delivery 2, small pelvis 2 and pre-eclampsia 2. Post-partum complications occurred in 28% of the mothers: infection 3, bleeding requiring curettage or operation 3, anaemia requiring blood transfusion 5 and rupture of anal sphincter 1. One mother who delivered normally at 41 weeks of gestation was diagnosed with placenta accreta, and a total abdominal hysterectomy was required because of profuse bleeding. She recovered well.
Neonatal outcome
Forty-six infants (40 singletons and 6 multiples) were born. In all, 30 (65%) of the infants were girls and 16 (35%) were boys. Data on the neonatal outcome are summarized in Table II. Only two of the infants had a birthweight below 2500 g (4.3%), and three were small for gestational age (SGA) (6.5%). One girl had transient brachial plexus palsy as a consequence of shoulder dystocia. She recovered completely by 6 months of age. No major or minor malformations were observed among the children.
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Physical growth of the children
The three SGA children had caught up the normal growth charts by 1 year of age. The mean height of the girls at 12 months was +0.2 SD (range –1.0 to +2.6) and that of the boys +0.2 SD (range –1.0 to +2.5). The mean height-related weights at 12 months were –1.8 percentiles (range –14 to +11) for girls and +2.3 percentiles (range –7 to +12) for boys. The mean height at 2 years was +0.1 SD (range –2.0 to +2.3) for girls and +0.2 SD (range –0.6 to +0.6) for boys. The mean height-related weights at 2 years were +1.1 percentiles (range –14 to +20) for girls and –1.3 percentiles (range –10 to +7) for boys. Two of the girls had a weight below the –10% line at 1 year of age and one of them still at 2 years. Respectively, two of the girls were slightly overweight at 2 years of age, with weights of 16 kg (+19%) and 17 kg (+20%).
Neurological and neuropsychological outcome
The developmental outcome of the children is shown in Figure 1. Forty-one children were examined at 6 months of age. Three of them (7%) demonstrated MDD, with a delay in only one or two fields of development.
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At the age of 12 months, 43 children had the neurological assessment completed, and three children were lost to follow-up because the families moved abroad during the study.
One girl demonstrated CDD and nystagmus, whereas at 6 months, this child had showed normal development. In further investigations, a glioma of the optic nerve was found. She had no café au lait lesions, and her parents demonstrated no signs of neurofibromatosis. Eight children (19%) showed MDD in one to three developmental fields (Figure 1). The neurological outcome of the children with developmental delay is summarized in Table III.
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At the age of 24 months, the Bayley Scale of Infants was completed in 35 children. The mean MDI of the girls (n = 22) was 106 (range 82–120) and that of the boys (n = 13) 101 (range 92–114). Only one child fell in the group of minor delay, with an MDI of 82. Nine of the children are still younger than 2 years.
The relationships between developmental outcome at 1 and 2 years of age and different risk factor variables were analysed by multilinear regression analysis. None of the parameters, gestational age at delivery, duration of infertility, fertilization by IVF or ICSI, complications during pregnancy, sex of the infant, SGA, Apgar score at 5 min, mode of delivery (CS or vaginal) and treatment in neonatal intensive care unit/neonatal ward, influenced the development of the IVM children.
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Discussion |
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This study includes all live births obtained by IVM at our clinic until April 2004 and is the first to present preliminary follow-up data on IVM children. At the start of this project, we decided not to recruit spontaneous or IVF pregnancies as controls because we used standardized follow-up methods for growth and development, and, therefore, the results could be compared with well-documented Finnish national standards. IVM has been used for various indications of infertility using both IVM–IVF and IVM–ICSI. Analysis for background risk factors, such as the mode of fertilization, did not show differences in perinatal or infant outcome (data not shown), and, therefore, the results are uniformly presented for all patients. To date, nine of the children included in this study are still younger than 2 years of age. However, because the IVM technique is still very new, we feel that it is important to present this preliminary follow-up data on the children at this point in time.
ART pregnancies are known to be associated with increased risk of obstetric and neonatal complications (Helmerhorst et al., 2004; Jackson et al., 2004; Schieve et al., 2004). The poorer outcome in ART pregnancies compared to that of spontaneous pregnancies has been explained by a higher frequency of multiple pregnancies, maternal characteristics, underlying subfertility (Olivennes et al., 1993; Bergh et al., 1999), influence of ovarian stimulation (Olivennes et al., 1993) and the phenomenon of vanishing twins (Pinborg et al., 2005). Furthermore, there has been some concern about health risks of imprinting disorders in children born after ART (Gosden et al., 2003; Maher et al., 2003). Placenta praevia, gestational diabetes and pre-eclampsia occur significantly more often in singleton IVF pregnancies than in controls (Wang et al., 2002; Jackson et al., 2004). The risk of preterm birth (5.8–15%) in standard IVF singletons is twice that of natural conceptions (Helmerhorst et al., 2004). There is very limited data available on the obstetric outcome of IVM children. Preterm delivery rate of 4.3–12.5% of IVM patients has been reported (Cha et al., 2005; Mikkelsen, 2005). The preterm birth rate was low among our IVM mothers as only two of the singleton pregnancies (5%) ended prematurely at 35–36 weeks gestation. The CS rate of 35% seen in this study compared well with figures (33–46%) reported from other IVM programmes (Cha et al., 2005; Mikkelsen, 2005). There are several possible explanations to the favourable obstetric and perinatal outcome in this study. The mothers were relatively young and without any basic health problems. As we transferred only one or two embryos at a time, the number of twin births and vanishing twins was low. Whether the absence of ovarian stimulation was advantageous as regards pregnancy outcome cannot be answered by this study, but this remains a possibility.
The mean birthweight of our IVM infants (singletons 3550 g and twins 2622 g) was within a normal range for Finnish newborns. According to National Research and Development Centre for Welfare and Health in Finland, the mean birthweight of all newborns including 3% multiples has been 3507–3519 g during 2000–2003 (Vuori and Gissler, 2004). During 1998–1999, the mean birthweight of Finnish IVF singletons was 3438 g and that of non-IVF singletons 3549 g (Klemetti et al., 2002). In singleton IVF pregnancies, the risk of low birthweight has been estimated to be 2.9–15.7% and that of SGA babies 1.6–16.3% (Helmerhorst et al., 2004). The birthweight of all our IVM singleton newborns was above 2500 g, and the SGA rate was low. The proportion of newborns with birthweight 
4000 g (13.0%) was lower than that of the general Finnish population (19%) (Vuori and Gissler, 2004). Other investigators have also found normal birthweight in IVM infants (Cha et al., 2005; Mikkelsen, 2005).
Only six newborns (13%) were admitted to a neonatal surveillance or an intensive care unit. This admittance rate is lower than that of Finnish IVF newborns (25%) in general (Klemetti et al., 2002). A conspicuous finding was that the number of boys in this series was lower than expected. However, in other IVM programmes, the male infants have been in a slight majority (Cha et al., 2005; Mikkelsen, 2005). When the number of IVM children increases, this gender imbalance is likely to disappear.
Earlier reports have revealed a slightly increased incidence of congenital malformations in children born after IVF or ICSI (Bergh et al., 1999; Silver et al., 1999; Ericson and Källén, 2001; Hansen et al., 2002; Koivurova et al., 2002). The increased risk has at least partly been related to paternal characteristics and to excess preterm and multiple births (Pinborg et al., 2004; Aittomäki et al., 2005). Cha et al. (2005) reported major congenital anomalies in two IVM infants (5.3%). In our study, there were no major malformations found in the children up to 2 years of age, but minor malformations might have been missed as no ultrasound examinations were systematically made after birth. It is possible that the low number of twins diminished the risk for malformations.
Three children in our series showed minor developmental delay at the age of 6 months. Two of them had caught up the normal developmental profile by the age of 12 months. However, at the age of 12 months, nine children expressed mild developmental problems. The relatively high proportion of MDD (19%) according to our strict criteria for normal development was higher than that of 10% usually reported in the general Finnish population (Autti-Rämö and Granström, 1991; Salokorpi et al., 1998). The reason for this increased rate of MDD cannot easily be explained. Multilinear regression analysis did not show any correlation with parental characteristics, mode of fertilization or obstetric and perinatal risk factors. Absence of statistical significance might, however, be because of the small sample size.
Thus far, most follow-up studies of ART children have not shown any negative influence of the technology on child development (Olivennes et al., 1997, 2002; Bonduelle et al., 2003; Koivurova et al., 2003). There is only one report on a slightly negative effect of ICSI on motor development of children at 1 year of age (Bowen et al., 1998). When the same children were evaluated again at the age of 5 years, there was no negative influence seen (Leslie et al., 2003). Currently, in our study, all children with MDD or CDD at 1 year of age have been examined at the age of 2 years. Eight of them have shown normal neuropsychological development compared to the standard population, whereas only one girl fell in the group of minor delay. As the development of the children was normal at 2 years of age, it is difficult to speculate the relevance of the high proportion of MDD at 1 year of age. Clearly, further studies will be needed to be able to answer this question.
Only one child in our study was unhealthy, with CDD at the age of 12 months. This girl had nystagmus and visual and motor problems because of an optical glioma. Thus far, no increased risk of childhood cancer has been found in IVF children (Bergh et al., 1999; Bruinsma et al., 2000; Klip et al., 2001). Retinoblastoma may be an exception, as five times more cases than expected have been reported from the Netherlands (Moll et al., 2003). Another previous paper has also concluded that children born after IVF and ICSI had an increased incidence of ocular anomalies (Anteby et al., 2001). Whether our single case of optical glioma is related to IVM or not remains to be seen.
This study is the first to present preliminary follow-up data of IVM children. We can conclude that the obstetric and perinatal outcome was good. The mean birthweight of the infants was within the normal range, with no singleton low-birth newborns and very few SGA babies. A small number of twin births and a low incidence of ART-connected complications, such as preterm delivery, affected probably the perinatal outcome positively. The IVM children showed more than expected minor developmental delays at 1 year of age. However, preliminary results of child growth and development at 2 years of age were normal.
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Acknowledgements |
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The study was sponsored by Medi-Cult a/s and supported by a grant from the Medical Society of Finland. We are grateful to Helena Korpelainen for the statistical analysis and psychologist Riina Pousi for her help in examining the children at 2 years of age.
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References |
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Submitted on October 6, 2005; resubmitted on December 16, 2005; accepted on December 23, 2005.
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