Browsing by Subject "IN-VITRO FERTILIZATION"

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  • Iso-Touru, Terhi; Wurmser, Christine; Venhoranta, Heli; Hiltpold, Maya; Savolainen, Tujia; Sironen, Anu; Fischer, Konrad; Flisikowski, Krzysztof; Fries, Ruedi; Vicente-Carrillo, Alejandro; Alvarez-Rodriguez, Manuel; Nagy, Szabolcs; Mutikainen, Mervi; Peippo, Jaana; Taponen, Juhani; Sahana, Goutam; Guldbrandtsen, Bernt; Simonen, Henri; Rodriguez-Martinez, Heriberto; Andersson, Magnus; Pausch, Hubert (2019)
    Background: Cattle populations are highly amenable to the genetic mapping of male reproductive traits because longitudinal data on ejaculate quality and dense microarray-derived genotypes are available for thousands of artificial insemination bulls. Two young Nordic Red bulls delivered sperm with low progressive motility (i.e., asthenospermia) during a semen collection period of more than four months. The bulls were related through a common ancestor on both their paternal and maternal ancestry. Thus, a recessive mode of inheritance of asthenospermia was suspected. Results: Both bulls were genotyped at 54,001 SNPs using the Illumina BovineSNP50 Bead chip. A scan for autozygosity revealed that they were identical by descent for a 2.98Mb segment located on bovine chromosome 25. This haplotype was not found in the homozygous state in 8557 fertile bulls although five homozygous haplotype carriers were expected (P=0.018). Whole genome-sequencing uncovered that both asthenospermic bulls were homozygous for a mutation that disrupts a canonical 5 splice donor site of CCDC189 encoding the coiled-coil domain containing protein 189. Transcription analysis showed that the derived allele activates a cryptic splice site resulting in a frameshift and premature termination of translation. The mutated CCDC189 protein is truncated by more than 40%, thus lacking the flagellar C1a complex subunit C1a-32 that is supposed to modulate the physiological movement of the sperm flagella. The mutant allele occurs at a frequency of 2.5% in Nordic Red cattle. Conclusions; Our study in cattle uncovered that CCDC189 is required for physiological movement of sperm flagella thus enabling active progression of spermatozoa and fertilization. A direct gene test may be implemented to monitor the asthenospermia-associated allele and prevent the birth of homozygous bulls that are infertile. Our results have been integrated in the Online Mendelian Inheritance in Animals (OMIA) database (
  • Huang, Jonathan Yinhao; Cai, Shirong; Huang, Zhongwei; Tint, Mya Thway; Yuan, Wen Lun; Aris, Izzuddin M.; Godfrey, Keith M.; Karnani, Neerja; Lee, Yung Seng; Chan, Jerry Kok Yen; Chong, Yap Seng; Eriksson, Johan Gunnar; Chan, Shiao-Yng (2021)
    Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen. Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD [95% CI: -0.7, -0.2]), lighter (-0.6 SD [-0.9, -0.3]) and have lower skinfold thicknesses (e.g. -14% [-24%, -3%] suprailiac), and blood pressure (-3 mmHg [-6, -0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.
  • Terho, Anna Maria; Pelkonen, Sari; Toikkanen, Ronja; Koivurova, Sari; Salo, Jarmo; Nuojua-Huttunen, Sinikka; Pokka, Tytti; Gissler, Mika; Tiitinen, Aila; Martikainen, Hannu (2021)
    Research question: Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? Design: Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. Results: Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. Conclusions: Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.
  • Wennberg, Anna Lena; Opdahl, Signe; Bergh, Christina; Henningsen, Anna-Karina Aaris; Gissler, Mika; Romundstad, Liv Bente; Pinborg, Anja; Tiitinen, Aila; Skjaerven, Rolv; Wennerholm, Ulla-Britt (2016)
    Objective: To compare the effect of maternal age on assisted reproductive technology (ART) and spontaneous conception (SC) pregnancies regarding maternal and neonatal complications. Design: Nordic retrospective population-based cohort study. Data from national ART registries were cross-linked with national medical birth registries. Setting: Not applicable. Patient(s): A total of 300,085 singleton deliveries: 39,919 after ART and 260,166 after SC. Intervention(s): None. Main Outcome Measure(s): Hypertensive disorders in pregnancy (HDP), placenta previa, cesarean delivery, preterm birth (PTB; = 28 weeks). Adjusted odds ratios (AORs) were calculated. Associations between maternal age and outcomes were analyzed. Result(s): The risk of placenta previa (AOR 4.11-6.05), cesarean delivery (AOR 1.18-1.50), PTB (AOR 1.23-2.19), and LBW (AOR 1.44-2.35) was significantly higher in ART than in SC pregnancies for most maternal ages. In both ART and SC pregnancies, the risk of HDP, placenta previa, cesarean delivery, PTB, LBW, and SGA changed significantly with age. The AORs for adverse neonatal outcomes at advanced maternal age (>35 years) showed a greater increase in SC than in ART. The change in risk with age did not differ between ART and SC for maternal outcomes at advanced maternal age. Conclusion(s): Having singleton conceptions after ART results in higher maternal and neonatal outcome risks overall, but the impact of age seems to be more pronounced in couples conceiving spontaneously. (C) 2016 by American Society for Reproductive Medicine.
  • Niinimaki, Maarit; Veleva, Zdravka; Martikainen, Hannu (2015)
    Objective: The study was aimed to evaluate which factors affect the cumulative live birth rate after elective single embryo transfer in women younger than 36 years. Additionally, number of children in women with more than one delivery per ovum pick-up after fresh elective single embryo transfer and subsequent frozen embryo transfers was assessed. Study design: Retrospective cohort study analysing data of a university hospital's infertility clinic in 2001-2010. A total of 739 IVF/ICSI cycles with elective single embryo transfer were included. Analyses were made per ovum pick-up including fresh and subsequent frozen embryo transfers. Factors affecting cumulative live birth rates were examined in uni- and multivariate analyses. A secondary endpoint was the number of children born after all treatments. Results: In the fresh cycles, the live birth rate was 29.2% and the cumulative live birth rate was 51.3%, with a twin rate of 3.4%. In the multivariate analysis, having two (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.12-2.67) or >= 3 top embryos (OR 2.66; 95% CI 1.79-3.95) was associated with higher odds for live birth after fresh and frozen embryo cycles. Age, body mass index, duration of infertility, diagnosis or total gonadotropin dose were not associated with the cumulative live birth rate. In cycles with one top embryo, the cumulative live birth rate was 40.2%, whereas it was 64.1% in those with at least three top embryos. Of women who had a live birth in the fresh cycle, 20.4% had more than one child after all frozen embryo transfers. Among women with three or more top embryos after ovum pick-up, 16.1% gave birth to more than one child. Conclusion: The cumulative live birth rate in this age group varies from 40% to 64% and is dependent on the quality of embryos. Women with three or more top embryos have good chance of having more than one child per ovum pick-up without elevated risk of multiple pregnancies. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Henningsen, A. A.; Gissler, M.; Rasmussen, S.; Opdahl, S.; Wennerholm, U. B.; Spangmose, A. L.; Tiitinen, A.; Bergh, C.; Romundstad, L. B.; Laivuori, H.; Forman, J. L.; Pinborg, A.; Lidegaard, O. (2020)
    STUDY QUESTION: Is the risk of imprinting disorders increased in children conceived after ART? SUMMARY ANSWER: We found an adjusted odds ratio (AOR) of 2.84 [95% CI: 1.34-6.01] for Beckwith-Wiedemann syndrome in ART children, while the risk of Prader-Willi syndrome, Silver-Russell syndrome or Angelman syndrome was not increased in children conceived after ART. WHAT IS KNOWN ALREADY: Earlier studies, most of them small, have suggested an association between ART and imprinting disorders. STUDY DESIGN, SIZE, DURATION: This was a binational register-based cohort study. All children conceived by ART in Denmark (n = 45 393, born between 1994 and 2014) and in Finland (n = 29 244, born between 1990 and 2014) were identified. The full background populations born during the same time periods in the two countries were included as controls. Odds ratios of imprinting disorders in ART children compared with naturally conceived (NC) children were calculated. The median follow-up time was 8 years and 9 months for ART children and 11 years and 9 months for NC children. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the national health registries in Denmark and Finland, we identified all children diagnosed with Prader-Willi syndrome (n = 143), Silver-Russell syndrome (n = 69), Beckwith-Wiedemann syndrome (n = 105) and Angelman syndrome (n = 72) born between 1994/1990 and 2014, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a total of 388 children diagnosed with imprinting disorders; 16 of these were conceived after ART. The overall AOR for the four imprinting disorders in ART children compared with NC children was 1.35 [95% CI: 0.80-2.29], but since eight ART children were diagnosed with Beckwith-Wiedemann syndrome, the AOR for this specific imprinting disorder was 2.84 [95% CI: 1.34-6.01]. The absolute risk of Beckwith-Wiedemann syndrome in children conceived after ART was still low: 10.7 out of 100 000 newborns. The risks of Prader-Willi syndrome, Silver-Russell syndrome and Angelman syndrome were not increased in children conceived after ART. LIMITATIONS, REASONS FOR CAUTION: Imprinting disorders are rare events and our results are based on few ART children with imprinting disorders. The aetiology is complex and only partly clarified, and the clinical diagnoses are challenged by a broad phenotypic spectrum. WIDER IMPLICATIONS OF THE FINDINGS: In the existing studies, results on the risk of imprinting disorders in children conceived after ART are ambiguous. This study adds that the risk of imprinting disorders in ART children is very small and perhaps restricted to Beckwith-Wiedemann syndrome.
  • Barbuscia, Anna; Martikainen, Pekka; Myrskylä, Mikko; Remes, Hanna; Somigliana, Edgardo; Klemetti, Reija; Goisis, Alice (2020)
    STUDY QUESTION Does the risk of low birth weight and premature birth increase with age among mothers who conceive through medically assisted reproduction (MAR)? SUMMARY ANSWER Among MAR mothers, the risk of poorer birth outcomes does not increase with maternal age at birth except at very advanced maternal ages (40+). WHAT IS KNOWN ALREADY The use of MAR treatments has been increasing over the last few decades and is especially diffused among women who conceive at older ages. Although advanced maternal age is a well-known risk factor for adverse birth outcomes in natural pregnancies, only a few studies have directly analysed the maternal age gradient in birth outcomes for MAR mothers. STUDY DESIGN, SIZE, DURATION The base dataset was a 20% random sample of households with at least one child aged 0-14 at the end of 2000, drawn from the Finnish population register and other administrative registers. This study included children who were born in 1995-2000, because the information on whether a child was conceived through MAR or naturally was available only from 1995 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS The outcome measures were whether the child had low birth weight (LBW, MAIN RESULTS AND THE ROLE OF CHANCE A total of 56026 children, 2624 of whom were conceived through MAR treatments, were included in the study. Among the mothers who used MAR to conceive, maternal age was not associated with an increased risk of LBW (the overall prevalence was 12.6%) at ages 25-39. For example, compared to the risk of LBW at ages 30-34, the risk was 0.22 percentage points lower (95% CI: -3.2, 2.8) at ages 25-29 and was 1.34 percentage points lower (95% CI: -4.5, 1.0) at ages 35-39. The risk of LBW was increased only at maternal ages >= 40 (six percentage points, 95% CI: 0.2, 12). Adjustment for maternal characteristics only marginally attenuated these associations. In contrast, among the mothers who conceived naturally, the results showed a clear age gradient. For example, compared to the risk of LBW (the overall prevalence was 3.3%) at maternal ages 30-34, the risk was 1.1 percentage points higher (95% CI: 0.6, 1.6) at ages 35-39 and was 1.5 percentage points higher (95% CI: 0.5, 2.6) at ages >= 40. The results were similar for preterm births. LIMITATIONS, REASON FOR CAUTION A limited number of confounders were included in the study because of the administrative nature of the data used. Our ability to reliably distinguish mothers based on MAR treatment type was also limited. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to analyse the maternal age gradient in the risk of adverse birth outcomes among children conceived through MAR using data from a nationally representative sample and controlling for important maternal health and socio-economic characteristics. This topic is of considerable importance in light of the widespread and increasing use of MAR treatments.
  • Marjonen, Heidi Maria; Auvinen, Pauliina; Kahila, Hanna; Tšuiko, Olga; Kõks, Sulev; Tiirats, Airi; Viltrop, Triin; Tuuri, Timo; Söderström-Anttila, Viveca; Suikkari, Anne-Maria; Salumets, Andres; Tiitinen, Aila; Kaminen-Ahola, Nina (2018)
    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 (1GF2)/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.
  • Henningsen, Anna-Karina A.; Bergh, Christina; Skjaerven, Rolv; Tiitinen, Aila; Wennerholm, Ulla-Britt; Romundstad, Liv B.; Gissler, Mika; Opdahl, Signe; Andersen, Anders Nyboe; Lidegaard, Ojvind; Forman, Julie L.; Pinborg, Anja (2018)
    IntroductionChildren born after assisted reproductive technology, particularly singletons, have been shown to have an increased risk of congenital malformations compared with children born after spontaneous conception. We wished to study whether there has been a change in the past 20 years in the risk of major congenital malformations in children conceived after assisted reproductive technology compared with children spontaneously conceived. Material and methodsPopulation-based cohort study including 90 201 assisted reproductive technology children and 482 552 children spontaneously conceived, born in Denmark, Finland, Norway and Sweden. Both singletons and twins born after in vitro fertilization, intracytoplasmatic sperm injection and frozen embryo transfer were included. Data on children were taken from when the national Nordic assisted reproductive technology registries were established until 2007. Multiple logistic regression analyses were used to estimate the risks and adjusted odds ratios for congenital malformations in four time periods: 1988-1992, 1993-1997, 1998-2002 and 2003-2007. Only major malformations were included. ResultsThe absolute risk for singletons of being born with a major malformation was 3.4% among assisted reproductive technology children vs. 2.9% among children spontaneously conceived during the study period. The relative risk of being born with a major congenital malformation between all assisted reproductive technology children and children spontaneously conceived remained similar through all four time periods (p = 0.39). However, we found that over time the number of children diagnosed with a major malformation increased in both groups across all four time periods. ConclusionWhen comparing children conceived after assisted reproductive technology and spontaneously conceived, the relative risk of being born with a major congenital malformation did not change during the study period.