Assisteret befrugtning (ART) Fremtidens Børn Anja Pinborg, professor, dr.med. Fertility Clinic, Dept. of Obs & Gyn Hvidovre Hospital, University of Copenhagen, Denmark
6 millioner børn født efter assisteret befrugtning 8% efter fertilitetsbehandling i Danmark 5% efter IVF/ICSI i Danmark
INDHOLD ART tvillinger ART og epigenetik Det infertile par Ovarie stimulation Laboratorieteknik Long-term follow-up
ART - Tvillinger
ART tvillingeraten 18.6% i Europa i 2011 Australia 6.5% (Kupka MS, et al. Hum Reprod 2016) 5
Dansk Fertilitetsselskab (www.fertilitetsselskab.dk)
% 35 30 25 20 15 10 5 0 Proportion of ART twin births Sweden Denmark Finland Norway 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 % 30 28 26 24 22 20 18 16 14 12 0 Preterm birth among ART children Sweden Denmark Finland Norway 1988 1992 1993 1997 1998 2002 2003 2007 Year 7
Hvorfor følge op på børnene født efter assisteret befrugtning? Selvregulering / selvkontrol Høj kvalitet Bedre end regulering og lovgivning Høj anseelse og respekt i samfundet Sikre kontrol af nye teknikker
ART - Epigenetik
Fra oocyt til embryon Ægudtagning Oplægning 24 hours 48 hours 5-6 days
DNA methylering under gametogenesen og inden implantationen Michelle M Denomme, and Mellissa R W Mann Reproduction 2012;144:393-409 2012 Society for Reproduction and Fertility Navn (Sidehoved/fod)
Epigenetik og ART børn Epigenetik og ART_Dec 2014
ART Forældre karakteristika
Alle dødsfald relateret til IVF behandling fra 1984 til 2008 17 dødsfald relateret til IVF graviditet (42.5/100,000) 8 ud ad 17 dødsfald var relateret til tvillingegraviditet Total mortalitet var lavere blandt kvinder, som havde været i IVF behandling Total maternel mortalitet var højere ved IVF graviditeter end i baggrundspopulationen
Mortalitet blandt 42,915 kvinder i Danmark behandlet med ART 2.5 *All odds ratios were adjusted for socio-economic status 2.0 2.16 1.5 1.0 0.5 0.47 0.63 0.43 0.48 0.30 0.20 0.35 0.0 (Petersen GL, et al. ESHRE, 7 10 July, London, 2013)
Myten om det infertile par Ældre Nullipara Færre rygere BMI ligner baggrundspopulationen Reproduktiv sygdom Sygdomme i æg- og sædceller Y-kromosom deletioner Epigenetisk modulation
Risiko for præterm fødsel blandt singletons født af subfertile par (Time-to-pregnancy >1 år) % Study AOR (95% CI) Weight Basso et al, 2003, Denmark 1.36 (1.08, 1.71) 19.12 Thomson et al, 2005, Scotland 1.50 (1.30, 1.80) 35.63 Wisborg et al, 2010, Denmark 1.19 (0.98, 1.44) 26.47 Jaques et al, 2012, Australia 1.32 (1.05, 1.67) 18.78 Overall (I-squared = 9.0%, p = 0.348) 1.35 (1.22, 1.50) 100.00.8 1 1.2 1.4 1.6 1.8 Gyn/Obs Afd. Hvidovre Hospital 10.januar 2014
Risiko for præterm fødsel i ART/non-ART singleton søskende par
ESHRE Campus Course, Lisbon 27.Sept 2014
ART Ovarie stimulation
Alle friske IVF behandlinger fra 1991 2008 (HFEA data) Kvinder med >20 oocytter havde højere risiko for præterm fødsel og lav fødselsvægt Multiple gestationssække som førte til singleton fødsel havde højere risiko for præterm fødsel og lav fødselsvægt Anovulatoriske tilstande var associeret med dårligere obstetrisk udkomme 1. Sazonoa A, et al. Hum Reprod 2011; 26:442 50 2. Baker VL, et al. Fertil Steril 2014;103:931 8
Præterm fødsel (a) og lav fødselsvægt (c) associeret til antal udtagne æg i 65,868 ART singletons Præterm fødsel AOR 1.15 (95% CI: 1.03 1.28) Lav fødselsvægt AOR 1.17 (95% CI: 1.05 1.30)
ART Laboratoriet
ESHRE Campus Course, Lisbon 27.Sept 2014 (2348 FET and 8944 fresh singletons born 2002-2006) FET vs. fresh Crude OR (95%CI) Adjusted OR (95%CI) 1500 g 1.00 (0.66 1.51) 1.07 (0.70 1.63) 2500 g 0.71 (0.57 0.89) 0.76 (0.60 0.95) 4500 g 1.48 (1.18 1.87) 1.46 (1.15 1.85) 5500 g 1.27 (0.13 12.2) 0.84 (0.08 8.62) SGA 0.72 (0.54 0.96) 0.78 (0.58 1.04) LGA (>+2 SD) 1.74 (1.39 2.16) 1.59 (1.26 1.99) Pre-eclampsia 1.21 (0.99 1.50) 1.32 (1.07 1.63)
Large-for-Gestational-Age (LGA) Frozen vs. fresh Frozen vs. natural conception OR 1.54 (95% CI: 1.31 1.81) OR 1.32 (95% CI: 1.07 1.61) Forest plot of pooled estimate of being born LGA (z-score >2 SD) in singletons conceived after frozen embryo transfer versus those conceived after fresh embryo transfer Forest plot of pooled estimate of being born LGA (z-score >2 SD) in singletons conceived after frozen embryo transfer versus naturally conceived singletons 27
Dyrkningsmedier og fødselsvægt Dumoulin 2010; Nelissen 2012 Vitrolife versus Cook medium BW difference 245 gram (P=0.003) BW difference Z-score (correction for sex and gestational age)(p =0.001) Eaton 2012; Vergouw 2012; Lin 2013; Carrasco 2013; Lemmen 2013 Culture medium not associated with BW 245 g Paediatric Research_Ph.D.course_29.April 2015_15.15-16.00
Præterm fødsel efter blastocyst (n=21,459) vs. cleavage stage transferering (n=55,736)
ART Trends over time
Preterm birth in ART singleton and twins % % 14 70 CoNARTaS Committee of Nordic ART and Safety 12 10 60 50 National data from Sweden, Finland, Norway and Denmark 8 6 40 30 92,000 ART children 4 Singletons Twins 20 IVF, ICSI, fryss æg (FER) 2 Assisted Spontaneous Assisted Spontaneous 10 0 0 31
Meta-analyser og medfødte misdannelser blandt ART børn Study Year Studies accepted OR (95% CI) Rimm et al 2004 19 1.29 (1.01 1.67) Hansen et al 2005 25* 1.29 (1.21 1.37) Wen et al 2012 46 1.37 (1.26 1.48) Hansen et al 2013 45* 1.32 (1.24 1.42) *Many studies considered acceptable in the 2005 review by Hansen et al were no longer considered acceptable in their 2013 report
Large population-based studies on congenital anomalies in ART pregnancies (2005 2013) Study Years of sample accrual Adjusted OR (95% CI) Statistical significance Country Kallen et al 1982 2001 1.44 (1.32 1.57) Yes Sweden Davies et al 1986 2002 1.24 (1.09 1.41) Yes Australia (Adelaide) Halliday et al 1991 2004 1.36 (1.19 1.55) Yes Australia (Parkville) Hansen et al 1994 2002 1.53 (1.30 1.79) Yes Australia (Perth) Pinborg et al 1995 2000 1.24 (0.97 1.58) No Denmark Klemetti et al 1996 1999 1.31 (1.10 1.57) Yes Finland Ombelet et al 1997 2003 1.11 (0.08 1.58) No Belgium Kallen et al 2001 2007 1.25 (1.15 1.37) Yes Sweden Kelley-Quon et al 2006 2007 1.25 (1.21 1.39) Yes USA (California) Fuji et al 2006 1.17 (0.81 1.69) No Japan 34
ART Long term outcomes
Hazard ratio (95% CI) for cancer in children born after ART vs non-art ART n Non-ART n Crude* Any cancer 178 643 1.16 (0.98-1.37) Adjusted** 1.15 (0.97-1.35) *Age at diagnosis and time of follow-up incorporated **Adjustment for country
IVF singletons (n=65) and spontaneously conceived singletons (n=57) General vascular dysfunction in the systemic and pulmonary circulation Intima thickness in the carotic artery Pressure in the pulmonary artery
Diastolic and systolic BP Fat deposits Fasting glucose Fasting insulin, lipids Bone age
Paediatric Research_Ph.D.course_29.April 2015_15.15-16.00
Hazard rates and 95% CIs for mental disorders * in children aged 0 17 years according to type of infertility treatment, hormones, gametes and aetiology of infertility compared with spontaneously conceived children No of exposed Any psychiatric diagnosis (n=23,278) Mental retardation (n=3371) Disorders of psychological development (n=11,794) Behaviour and emotional disorders (n=16,432) Other/unspecified psychiatry disorders (n=682) Procedure OI/IUI 18,148 1.20 (1.11 to 1.31) 1.02 (0.81 to 1.28) 1.17 (1.05 to 1.31) 1.22 (1.11 to 1.34) 1.16 (0.72 to 1.87) IVF 9532 1.01 (0.90 to 1.15) 0.88 (0.63 to 1.24) 0.98 (0.83 to 1.150 1.06 (0.91 to 1.23) 1.14 (0.56 to 2.29) ICSI 4201 1.08 (0.90 to 1.31) 0.81 (0.47 to 1.42) 1.17 (0.92 to 1.49) 1.10 (0.87 to 1.38) 0.33 (0.05 to 2.45) *As defined by ICD-10 (applicable in study period); adjusted for maternal age, parity, education al level, smoking in pregnancy, maternal psychiatric history, birth year, child s sex and multipclicity; specific type of treatment missing in 117 children in IVF/ICSI group; 163 had egg donation and 978 were fertilised with frozen egg without specification of treatment type (IVF or ICSI).
Academic performance in ART adolescents aged 15 16 years National birth cohorts 1995 1998 National test scores at 9th grade at primary school More than 90% of a cohort takes the exam Mean test scores, Danish, Mathematics, Science, Foreign language 7 is mean (-3 to 12) corresponding to C ART singletons vs. non-art singletons ART singletons vs. ART twins Pedersen AL, et al. Oral presentation at ESHRE, 14 17 June, Lisbon, Portugal, 2015
Academic performance in ART Adolescents aged 15-16 years - National Cohort Study (Pedersen et al., ESHRE 2015) ART singletons N=2544 Non-ART singletons N=4985 ART twins N=1676 Singletons ART vs. Non- ART P-values ART Singletons vs. Twins Test score, mean (SD) 7.16 (2.41) 6.74 (2.46) 7.21 (2.31) <0.01 0.47 *After adjustment for educational level and SES differences disappeared 42
ART Key Messages Obstetriske og perinatal outcomes 1.5-2 Misdannelsesrisiko 1.15-1.3 Kromosom anomalier (ICSI) 2.0 Cancer risiko er ikke øget Langtidseffekter? Akademiske kundskaber ligner gennemsnittet Perinatale risici er faldet over tid for ART børn
CoNARTaS ~ Committee of Nordic ART and Safety Aila Titiinen, Mika Gissler (Finland) Liv Bente Romundstad, Rolv Skjaerven (Norway) Ulla-Britt Wennerholm, Christina Bergh (Sweden) Anna-Karina Henningsen, Anja Pinborg (Denmark)
ART En god historie