The Association Between High Birth Weight and Long-Term Outcomes-Implications for Assisted Reproductive Technologies: A Systematic Review and Meta-Analysis.

Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences. Objective: The aim of this systematic review was to describe the association between high birth weight and LGA on long-term child outcomes. Data Sources: PubMed, Scopus, and Web of Science were searched up to January 2021. Exposure included high birth weight and LGA. Long-term outcome variables included malignancies, psychiatric disorders, cardiovascular disease, and diabetes. Study Selection: Original studies published in English or Scandinavian languages were included. Studies with a control group were included while studies published as abstracts and case reports were excluded. Data Extraction: The methodological quality, in terms of risk of bias, was assessed by pairs of reviewers. Robins-I (www.methods.cochrane.org) was used for risk of bias assessment in original articles. For systematic reviews, AMSTAR (www.amstar.ca) was used. For certainty of evidence, we used the GRADE system. The systematic review followed PRISMA guidelines. When possible, meta-analyses were performed. Results: The search included 11,767 articles out of which 173 met the inclusion criteria and were included in the qualitative analysis, while 63 were included in quantitative synthesis (meta-analyses). High birth weight and/or LGA was associated with low to moderately elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, and type 1 and 2 diabetes. Conclusions: Although the increased risks for adverse outcome in offspring associated with high birth weight and LGA represent serious health effects in childhood and in adulthood, the size of these effects seems moderate. The identified risk association should, however, be taken into account in decisions concerning fresh and frozen ART cycles and is of general importance in view of the increasing prevalence in high birthweight babies.

A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities.

BACKGROUND: In the decade following the introduction of ICSI, a higher prevalence of de novo chromosome abnormalities, in particular sex chromosome and autosomal structural abnormalities, as well as inherited abnormalities was described in children conceived by ICSI compared to both naturally conceived (NC) children and children conceived by standard IVF. The explanation for the observed increase in prevalence is not clear and has been suggested to reflect parental factors (e.g. age or sperm quality) or to be a result of the ICSI procedure itself. Over the years, the procedure, as well as the patient group, and indications for ICSI treatment have changed. OBJECTIVE AND RATIONALE: The objective of this systematic review and meta-analysis was to assess the prevalence of chromosome abnormalities in ICSI pregnancies and children and to examine any potentially increased risk compared to standard IVF and NC. SEARCH METHODS: Pubmed, Embase, Cochrane Libraries and Web of Science up to October 2020 were searched. Primary outcome measures were overall chromosome abnormalities and de novo abnormalities (including sex chromosome abnormalities and autosomal abnormalities). The secondary outcome was inherited abnormalities. We followed the PRISMA guidelines and relevant meta-analyses were performed. OUTCOMES: The search included 4648 articles, out of which 27 met the inclusion criteria, and 19 were included in quantitative synthesis (meta-analyses). The prevalence of chromosome abnormalities varied considerably between studies, possibly explained by large differences in sample size and patient demographics. Only five studies were eligible for pooled analyses on adjusted data. All studies had a critical risk of bias. Results from pooled adjusted data showed no evidence of an increased risk of overall chromosome abnormalities when comparing ICSI to either standard IVF (aOR 0.75 (95% CI 0.41-1.38)) or NC (aOR 1.29 (95% CI 0.69-2.43)). In contrast, meta-analyses on unadjusted data showed an increased risk of overall chromosome abnormalities in ICSI compared to both standard IVF (OR 1.42 (95% CI 1.09-1.85)) and NC (OR 2.46 (95% CI 1.52-3.99)) and an increased risk of de novo abnormalities in ICSI compared to NC (OR 2.62 (95% CI 2.07-3.31)). Yet, based on a very low certainty of evidence, the conclusion remains, that no indication of an increased risk of chromosome abnormalities in ICSI offspring could be found. If an increased risk of chromosome abnormalities in selected ICSI offspring should exist, the absolute risk continues to be small. WIDER IMPLICATIONS: This review provides an extensive overview of the existing evidence on the relationship between ICSI and chromosome abnormalities in the offspring. We highlight the need for well-designed large, prospective, controlled studies with systematic cytogenetic testing. Existing data are limited and, in many cases, marred by critical levels of bias.

In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages.

Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF)1-3, its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos4. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis5,6, a high number of embryos containing abnormal cells can pass this strong selection barrier7,8. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages.

The health of children conceived by ART: 'the chicken or the egg?'

Worldwide, more than 7 million children have now been born after ART: these delivery rates are steadily rising and now comprise 2-6% of births in the European countries. To achieve higher pregnancy rates, the transfer of two or more embryos was previously the gold standard in ART. However, recently the practise has moved towards a single embryo transfer policy to avoid multiple births. The positive consequences of the declining multiple birth rates after ART are decreasing perinatal risks and overall improved health for the ART progeny. In this review we summarize the risks for short- and long-term health in ART singletons and discuss if the increased health risks are associated with intrinsic maternal or paternal factors related to subfertility or to the ART treatments per se. Although the risks are modest, singletons born after ART are more likely to have adverse perinatal outcomes compared to spontaneously conceived (SC) singletons dependent on the ART method. Fresh embryo transfer is associated with a higher risk of small for gestational age babies (SGA), low birthweight and preterm birth (PTB), while frozen embryo transfer is associated with large-for-gestational age babies and pre-eclampsia. ICSI may be associated with a higher risk of birth defects and transferral of the poor semen quality to male progeny, while oocyte donation is associated with increased risk of SGA and pre-eclampsia. Concerning long-term health risks, the current evidence is limited but suggests an increased risk of altered blood pressure and cardiovascular function in ART children. The data that are available for malignancies seem reassuring, while results on neurodevelopmental health are more equivocal with a possible association between ART and cerebral palsy. The laboratory techniques used in ART may also play a role, as different embryo culture media give rise to different birthweights and growth patterns in children, while culture to blastocyst stage is associated with PTB. In addition, children born after ART have altered epigenetic profiles, and these alterations may be one of the key areas to explore to improve our understanding of adverse child outcomes after ART. A major challenge for research into adverse perinatal outcomes is the difficulty in separating the contribution of infertility per se from the ART treatment (i.e. 'the chicken or the egg'?). Choosing and having access to the appropriate control groups for the ART children in order to eliminate the influence of subfertility per se (thereby exploring the pure association between ART and child outcomes) is in itself challenging. However, studies including children of subfertile couples or of couples treated with milder fertility treatments, such as IUI, as controls show that perinatal risks in these cohorts are lower than for ART children but still higher than for SC indicating that both subfertility and ART influence the future outcome. Sibling studies, where a mother gave birth to both an ART and a SC child, support this theory as ART singletons had slightly poorer outcomes. The conclusion we can reach from the well designed studies aimed at disentangling the influence on child health of parental and ART factors is that both the chicken and the egg matter.

rs10732516 polymorphism at the IGF2/H19 locus associates with genotype-specific effects on placental DNA methylation and birth weight of newborns conceived by assisted reproductive technology.

Background: Assisted reproductive technology (ART) has been associated with low birth weight of fresh embryo transfer (FRESH) derived and increased birth weight of frozen embryo transfer (FET)-derived newborns. Owing to that, we focused on imprinted insulin-like growth factor 2 (IGF2)/H19 locus known to be important for normal growth. This locus is regulated by H19 imprinting control region (ICR) with seven binding sites for the methylation-sensitive zinc finger regulatory protein (CTCF). A polymorphism rs10732516 G/A in the sixth binding site for CTCF, associates with a genotype-specific trend to the DNA methylation. Due to this association, 62 couples with singleton pregnancies derived from FRESH (44 IVF/18 ICSI), 24 couples from FET (15 IVF/9 ICSI), and 157 couples with spontaneously conceived pregnancies as controls were recruited in Finland and Estonia for genotype-specific examination. DNA methylation levels at the H19 ICR, H19 DMR, and long interspersed nuclear elements in placental tissue were explored by MassARRAY EpiTYPER (n = 122). Allele-specific changes in the methylation level of H19 ICR in placental tissue (n = 26) and white blood cells (WBC, n = 8) were examined by bisulfite sequencing. Newborns' (n = 243) anthropometrics was analyzed by using international growth standards. Results: A consistent trend of genotype-specific decreased methylation level was observed in paternal allele of rs10732516 paternal A/maternal G genotype, but not in paternal G/maternal A genotype, at H19 ICR in ART placentas. This hypomethylation was not detected in WBCs. Also genotype-specific differences in FRESH-derived newborns' birth weight and head circumference were observed (P = 0.04, P = 0.004, respectively): FRESH-derived newborns with G/G genotype were heavier (P = 0.04) and had larger head circumference (P = 0.002) compared to newborns with A/A genotype. Also, the placental weight and birth weight of controls, FRESH- and FET-derived newborns differed significantly in rs10732516 A/A genotype (P = 0.024, P = 0.006, respectively): the placentas and newborns of FET-derived pregnancies were heavier compared to FRESH-derived pregnancies (P = 0.02, P = 0.004, respectively). Conclusions: The observed DNA methylation changes together with the phenotypic findings suggest that rs10732516 polymorphism associates with the effects of ART in a parent-of-origin manner. Therefore, this polymorphism should be considered when the effects of environmental factors on embryonic development are studied.

The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis.

BACKGROUND: Maternal factors, including increasing childbearing age and various life-style factors, are associated with poorer short- and long-term outcomes for children, whereas knowledge of paternal parameters is limited. Recently, increasing paternal age has been associated with adverse obstetric outcomes, birth defects, autism spectrum disorders and schizophrenia in children. OBJECTIVE AND RATIONALE: The aim of this systematic review is to describe the influence of paternal factors on adverse short- and long-term child outcomes. SEARCH METHODS: PubMed, Embase and Cochrane databases up to January 2017 were searched. Paternal factors examined included paternal age and life-style factors such as body mass index (BMI), adiposity and cigarette smoking. The outcome variables assessed were short-term outcomes such as preterm birth, low birth weight, small for gestational age (SGA), stillbirth, birth defects and chromosomal anomalies. Long-term outcome variables included mortality, cancers, psychiatric diseases/disorders and metabolic diseases. The systematic review follows PRISMA guidelines. Relevant meta-analyses were performed. OUTCOMES: The search included 14 371 articles out of which 238 met the inclusion criteria, and 81 were included in quantitative synthesis (meta-analyses). Paternal age and paternal life-style factors have an association with adverse outcome in offspring. This is particularly evident for psychiatric disorders such as autism, autism spectrum disorders and schizophrenia, but an association is also found with stillbirth, any birth defects, orofacial clefts and trisomy 21. Paternal height, but not BMI, is associated with birth weight in offspring while paternal BMI is associated with BMI, weight and/or body fat in childhood. Paternal smoking is found to be associated with an increase in SGA, birth defects such as congenital heart defects, and orofacial clefts, cancers, brain tumours and acute lymphoblastic leukaemia. These associations are significant although moderate in size, with most pooled estimates between 1.05 and 1.5, and none exceeding 2.0. WIDER IMPLICATIONS: Although the increased risks of adverse outcome in offspring associated with paternal factors and identified in this report represent serious health effects, the magnitude of these effects seems modest.

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.

Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

Short- and long-term health consequences and current satisfaction levels for altruistic anonymous, identity-release and known oocyte donors.

STUDY QUESTION: What are the short- and long-term health consequences and current satisfaction of altruistic oocyte donors? SUMMARY ANSWER: Donating oocytes in the majority (>90%) of donation cycles is not associated with harmful long-term general or reproductive health effects. WHAT IS KNOWN ALREADY: Knowledge of long-term health effects of oocyte donation on donors is sparse and follow-up studies have usually been carried out on commercial donors. Thus far, no major long-term harmful effects have been demonstrated. Most studies have reported a high level of donor satisfaction, but also less favorable experiences have been published. STUDY DESIGN, SIZE AND DURATION: A retrospective cross-sectional survey of all women who had donated oocytes between 1990 and 2012 at three fertility clinics was carried out in spring 2013. A self-administered questionnaire was sent out to a total of 569 former oocyte donors. PARTICIPANTS, SETTING, METHODS: In all, 428 past donors answered the questionnaire assessing donor's demographic characteristics, short- and long-term medical and psychological experiences and satisfaction related to donations. Of the donors, 87% (371/428) were unknown and 13% (57/428) were known to the recipient. The mean follow-up time after the donation was 11.2 years (range from 0.5 to 23 years) and the mean age of the respondents was 42 years at the time of the study. To learn whether the demographic profile of donors was affected by the Finnish Assisted Reproduction Technology (ART) Act of 2007, we divided the 428 respondents into two groups: (i) women whose first donation took place between 1990 and 2007 (79% of the respondents) and (ii) women whose first donation took place between 2008 and 2012 (21% of the respondents). Before 2008, donors were non-identifiable (anonymous) but after 2008 persons born as a result of gamete donation could, from the age of 18, receive on request information identifying the donor. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate was 75% (428/569). The mean age of the donors did not differ between the two time periods, but there was a higher proportion of donors in the youngest age group (20-24 years) and more childless donors (P < 0.05) after 2008 than between 1990 and 2007. Immediate complications occurred in 7.2% (42/582) of the donation cycles and the most common complication was ovarian hyperstimulation syndrome (OHSS) in 5.0% (29/582) of the treatments. There were no reports of ovarian or uterine cancer and only one case of breast cancer. After the donation, 11.5% of the donors experienced unsuccessful attempts to become pregnant. Almost all donors (99%) were satisfied or very satisfied with their decision to donate and 95% would warmly recommend it to other women. There were no differences between the known and unknown donors in this respect, or between the two time periods (before or after the ART Act in 2008). Four donors (1%) had regretted donation, and 7% would have wanted to have more support before and 14% after the donation. LIMITATIONS, REASON FOR CAUTION: Although the response rate was high, 25% of all former donors in the three participating clinics could not be included due to lack of response. The results are based on self-reported assessment of the experiences of former donors, and it is not possible to estimate the influence of recall bias. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the largest study of health consequences and satisfaction levels on oocyte donors. Data from this study can be used to inform donor candidates about the medical aspects involved in the treatment and it provides information on how to support these women during and after the donation. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the Medical Society Life and Health, and from the Otto A. Malm Foundation. There are no competing interests to report.

Epigenetics and assisted reproductive technologies.

Epigenetic modification controls gene activity without changes in the DNA sequence. The genome undergoes several phases of epigenetic programming during gametogenesis and early embryo development, coinciding with assisted reproductive technologies (ART) treatments. Imprinting disorders have been associated with ART techniques, but disentangling the influence of the ART procedures per se from the effect of the reproductive disease of the parents is a challenge. Epidemiological human studies have shown altered birthweight profiles in ART compared with spontaneously conceived singletons. Conception with cryopreserved/thawed embryos results in a higher risk of large-for-gestational-age babies, which may be due to epigenetic modification. Further animal studies have shown altered gene expression profiles in offspring conceived by ART related to altered glucose metabolism. It is controversial whether human adolescents conceived by ART have altered lipid and glucose profiles and thereby a higher long-term risk of cardiovascular disease and diabetes. This commentary describes the basic concepts of epigenetics and gives a short overview of the existing literature on the association between imprinting disorders, epigenetic modification and ART.

Surrogacy: outcomes for surrogate mothers, children and the resulting families-a systematic review.

BACKGROUND: Surrogacy is a highly debated method mainly used for treating women with infertility caused by uterine factors. This systematic review summarizes current levels of knowledge of the obstetric, medical and psychological outcomes for the surrogate mothers, the intended parents and children born as a result of surrogacy. METHODS: PubMed, Cochrane and Embase databases up to February 2015 were searched. Cohort studies and case series were included. Original studies published in English and the Scandinavian languages were included. In case of double publications, the latest study was included. Abstracts only and case reports were excluded. Studies with a control group and case series (more than three cases) were included. Cohort studies, but not case series, were assessed for methodological quality, in terms of risk of bias. We examined a variety of main outcomes for the surrogate mothers, children and intended mothers, including obstetric outcome, relationship between surrogate mother and intended couple, surrogate's experiences after relinquishing the child, preterm birth, low birthweight, birth defects, perinatal mortality, child psychological development, parent-child relationship, and disclosure to the child. RESULTS: The search returned 1795 articles of which 55 met the inclusion criteria. The medical outcome for the children was satisfactory and comparable to previous results for children conceived after fresh IVF and oocyte donation. The rate of multiple pregnancies was 2.6-75.0%. Preterm birth rate in singletons varied between 0 and 11.5% and low birthweight occurred in between 0 and 11.1% of cases. At the age of 10 years there were no major psychological differences between children born after surrogacy and children born after other types of assisted reproductive technology (ART) or after natural conception. The obstetric outcomes for the surrogate mothers were mainly reported from case series. Hypertensive disorders in pregnancy were reported in between 3.2 and 10% of cases and placenta praevia/placental abruption in 4.9%. Cases with hysterectomies have also been reported. Most surrogate mothers scored within the normal range on personality tests. Most psychosocial variables were satisfactory, although difficulties related to handing over the child did occur. The psychological well-being of children whose mother had been a surrogate mother between 5 and 15 years earlier was found to be good. No major differences in psychological state were found between intended mothers, mothers who conceived after other types of ART and mothers whose pregnancies were the result of natural conception. CONCLUSIONS: Most studies reporting on surrogacy have serious methodological limitations. According to these studies, most surrogacy arrangements are successfully implemented and most surrogate mothers are well-motivated and have little difficulty separating from the children born as a result of the arrangement. The perinatal outcome of the children is comparable to standard IVF and oocyte donation and there is no evidence of harm to the children born as a result of surrogacy. However, these conclusions should be interpreted with caution. To date, there are no studies on children born after cross-border surrogacy or growing up with gay fathers.

Obstetric and neonatal outcome after oocyte donation in 106 women with Turner syndrome: a Nordic cohort study.

STUDY QUESTION: What are the obstetric and neonatal outcomes of deliveries after oocyte donation (OD) in women with Turner syndrome (TS)? SUMMARY ANSWER: Pregnancies among women with TS carry a substantial risk, particularly for hypertensive disorders. Potentially life-threatening complications occurred in 3.3% of pregnancies. The neonatal outcomes were generally reassuring, with similar rates of preterm birth and low birthweight (LBW) as after conventional IVF and better than previously reported in deliveries after OD in women with TS. WHAT IS KNOWN ALREADY: OD pregnancies in women with TS are known to be high-risk pregnancies. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 106 women with TS who delivered after OD (n = 122 deliveries, n = 131 newborns) in three Nordic countries (Finland, Denmark, Sweden) between 1992 and 2011. PARTICIPANTS, SETTING AND METHODS: Women with TS who delivered after OD in three Nordic countries were identified (n = 110). Four women declined to participate or were lost to follow-up, thus 106 women were included in the study. The medical data from fertility clinics, antenatal clinics and the hospitals where the women had been treated and/or delivered were scrutinized. MAIN RESULTS AND THE ROLE OF CHANCE: In this cohort, the karyotype was 45,X in 44% of the women with TS. Ten women (9.4%) had a known cardiac defect before pregnancy. Single embryo transfer was performed in 70.3% of the cases and the multiple birth rate was 7.4%. In total, 35.0% of the pregnancies were associated with a hypertensive disorder including pre-eclampsia in 20.5%. Potentially life-threatening complications occurred in four pregnancies (3.3%), including one woman with aortic dissection, one with mild regurgitation of the tricuspid and mitral valve, one with a mechanical heart valve who developed HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and one who underwent a post-partum hysterectomy due to severe haemorrhaging. Neonatal outcomes were reassuring, with a preterm birth rate of 8.0% and LBW rate of 8.8% in singletons. Major birth defects were found in 3.8% of the children. The perinatal mortality was 2.3% (3/131), including a set of extremely preterm twins. LIMITATIONS, REASONS FOR CAUTION: Although this study was performed over a period of almost 20 years in three different countries, with a low drop-out rate and little missing data, much larger series are needed to assess rare events. This study also lacks an appropriate control group. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that cardiovascular evaluation before and during pregnancy may contribute to favourable obstetric outcomes in many cases. Maternal outcomes were in agreement with the literature while neonatal outcomes were generally better than previously reported. The outcomes were consistent across the three countries, supporting generalizability to similar populations.

Five years of single embryo transfer with anonymous and non-anonymous oocyte donation.

Single embryo transfer (SET) has been the main embryo transfer strategy in the oocyte donation programme at the authors' clinic since 2000. The primary aim of this study was to evaluate the effect of SET on the clinical outcome in an unselected group of oocyte recipients. A retrospective analysis of the outcome in 142 recipient cycles (116 from anonymous donors; 26 from known donors) was performed. The oocytes from each anonymous donor were shared between two recipients if at least 10 oocytes were obtained. The proportion of SET of all fresh transfers was 77.3%. The clinical pregnancy rate (CPR) was 43.2% and the delivery rate 31.1% per embryo transfer. The outcome was similar in recipients undergoing anonymous and non-anonymous donation. The delivery rates were similar after SET (30.4%) or double embryo transfer (DET) (33.3%), whereas the twin rate was 0% after SET and 40% after DET. The implantation rate was significantly better (P < 0.01) with good-quality embryos (54.7%) compared with non-optimal embryos (27.1%). Of 152 frozen-thawed embryo transfer cycles, 78.9% were SET. The CPR was 28.3% and the twin rate was 7.1%. In fresh oocyte donation cycles, elective SET can be recommended if the embryo quality is considered good, and always if there is a contraindication for twin pregnancy.

In-vitro maturation of eggs: is it really useful?

In in-vitro maturation (IVM), immature oocytes are collected from small antral follicles and allowed to mature in the laboratory before routine in-vitro fertilization or micro-injection. The authors' experience in IVM is based on the treatment of two main groups of patients: women with polycystic ovaries and women with normal ovaries. Patients with polycystic ovarian syndrome have irregular, mostly anovulatory cycles and are at increased risk for ovarian hyperstimulation syndrome because of their higher sensitivity to gonadotropins. Women with normal ovarian function may wish to avoid the side-effects of hormone injections, and therefore IVM has also been offered to couples with tubal, male factor and unexplained infertility. In all these groups of patients, immature oocytes have successfully been matured, fertilized and embryos transferred. Pregnancy rates have been reported to be between 4% and 54%. More than 300 children have been born and follow-up studies have reported no major concerns about the pregnancies, deliveries or health of the babies. There are still many questions concerning IVM. As the factors regulating follicle selection are poorly understood, no specific markers for the optimal time of immature oocyte collection have been defined. Furthermore, basic knowledge on the complex intracellular processes involved in the cytoplasmic maturation of human oocyte is lacking, making the design of optimal culture conditions for maturation difficult. The possible long-term effects of IVM on the health and development of children needs future study.

Obstetric and perinatal outcome and preliminary results of development of children born after in vitro maturation of oocytes.

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.

Genetics and assisted reproduction technology.

In the past 20 years, a significant improvement has been shown in the treatment for infertility in both women and men through the development of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Only donated sperm could be previously used for treatment; now oocytes can also be donated. Furthermore, the combination of IVF and ICSI with advanced genetic methods has made preimplantation genetic diagnosis possible for many genetic conditions. These methods enable genetic testing of the early human embryo by using only a single cell, one blastomere biopsied from the embryo, as the sample from which the diagnosis of many chromosome rearrangements and other inherited diseases can be made. It has also been established that a considerable proportion of infertility is caused by genetic defects, which have several implications for infertility treatment. The purpose of this review is to give a concise introduction on how genetics is involved in assisted reproduction technology to specialists who may not be working in this particular field of gynecology, but who would need some knowledge of this for proper care of their patients.

Favourable pregnancy results with insemination of in vitro matured oocytes from unstimulated patients.

BACKGROUND: The purpose has been to develop an in vitro oocyte maturation (IVM) method for a wide range of patients. METHODS: A total of 239 cycles with immature oocyte retrieval (IOC) were carried out without hormonal priming. Patients with regular cycles and normal or polycystic ovaries (PCO) and anovulatory cycles with PCOS were included. Insemination or intracytoplasmic sperm injection (ICSI) according to sperm quality was alternatively used in fertilization of the matured oocytes. RESULTS: A total of 971 immature oocytes (mean 8.0 +/- 5.2) were collected in 122 IVM-IVF cycles and 851 oocytes (mean 7.3 +/- 4.4) in 117 IVM-ICSI cycles. The oocyte maturation and fertilization rate was 62.6% and 37.7% after insemination, and 53.9% and 69.3% after ICSI, respectively. The mean number of embryos transferred was 1.6. Clinical pregnancy rate per IOC was 23.8% in IVM-IVF and 17.1% in IVM-ICSI (ns). Implantation rate was higher in IVM-IVF (24.2%) than in IVM-ICSI (14.8%) (P < 0.05). CONCLUSIONS: Insemination of IVM oocytes functions well, resulting in comparable pregnancy rates per IOC between IVM-IVF and IVM-ICSI. Good pregnancy results can be achieved both in patients with regular cycles and with PCO(S) by transferring only one or two embryos at a time.