Assisteret befrugtning (ART) Fremtidens Børn

Transkript

1 Assisteret befrugtning (ART) Fremtidens Børn Anja Pinborg, professor, dr.med. Fertility Clinic, Dept. of Obs & Gyn Hvidovre Hospital, University of Copenhagen, Denmark

2 6 millioner børn født efter assisteret befrugtning 8% efter fertilitetsbehandling i Danmark 5% efter IVF/ICSI i Danmark

3 INDHOLD ART tvillinger ART og epigenetik Det infertile par Ovarie stimulation Laboratorieteknik Long-term follow-up

4 ART - Tvillinger

5 ART tvillingeraten 18.6% i Europa i 2011 Australia 6.5% (Kupka MS, et al. Hum Reprod 2016) 5

6 Dansk Fertilitetsselskab (

7 % Proportion of ART twin births Sweden Denmark Finland Norway % Preterm birth among ART children Sweden Denmark Finland Norway Year 7

8 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

9 ART - Epigenetik

10 Fra oocyt til embryon Ægudtagning Oplægning 24 hours 48 hours 5-6 days

11 DNA methylering under gametogenesen og inden implantationen Michelle M Denomme, and Mellissa R W Mann Reproduction 2012;144: Society for Reproduction and Fertility Navn (Sidehoved/fod)

12 Epigenetik og ART børn Epigenetik og ART_Dec 2014

13 ART Forældre karakteristika

14 Alle dødsfald relateret til IVF behandling fra 1984 til 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

15 Mortalitet blandt 42,915 kvinder i Danmark behandlet med ART 2.5 *All odds ratios were adjusted for socio-economic status (Petersen GL, et al. ESHRE, 7 10 July, London, 2013)

16 Myten om det infertile par Ældre Nullipara Færre rygere BMI ligner baggrundspopulationen Reproduktiv sygdom Sygdomme i æg- og sædceller Y-kromosom deletioner Epigenetisk modulation

17 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) Thomson et al, 2005, Scotland 1.50 (1.30, 1.80) Wisborg et al, 2010, Denmark 1.19 (0.98, 1.44) Jaques et al, 2012, Australia 1.32 (1.05, 1.67) Overall (I-squared = 9.0%, p = 0.348) 1.35 (1.22, 1.50) Gyn/Obs Afd. Hvidovre Hospital 10.januar 2014

18 Risiko for præterm fødsel i ART/non-ART singleton søskende par

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20 ESHRE Campus Course, Lisbon 27.Sept 2014

21 ART Ovarie stimulation

22 Alle friske IVF behandlinger fra (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: Baker VL, et al. Fertil Steril 2014;103:931 8

23 Præterm fødsel (a) og lav fødselsvægt (c) associeret til antal udtagne æg i 65,868 ART singletons Præterm fødsel AOR 1.15 (95% CI: ) Lav fødselsvægt AOR 1.17 (95% CI: )

24 ART Laboratoriet

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26 ESHRE Campus Course, Lisbon 27.Sept 2014 (2348 FET and 8944 fresh singletons born ) FET vs. fresh Crude OR (95%CI) Adjusted OR (95%CI) 1500 g 1.00 ( ) 1.07 ( ) 2500 g 0.71 ( ) 0.76 ( ) 4500 g 1.48 ( ) 1.46 ( ) 5500 g 1.27 ( ) 0.84 ( ) SGA 0.72 ( ) 0.78 ( ) LGA (>+2 SD) 1.74 ( ) 1.59 ( ) Pre-eclampsia 1.21 ( ) 1.32 ( )

27 Large-for-Gestational-Age (LGA) Frozen vs. fresh Frozen vs. natural conception OR 1.54 (95% CI: ) OR 1.32 (95% CI: ) 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

28 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_

29 Præterm fødsel efter blastocyst (n=21,459) vs. cleavage stage transferering (n=55,736)

30 ART Trends over time

31 Preterm birth in ART singleton and twins % % CoNARTaS Committee of Nordic ART and Safety National data from Sweden, Finland, Norway and Denmark ,000 ART children 4 Singletons Twins 20 IVF, ICSI, fryss æg (FER) 2 Assisted Spontaneous Assisted Spontaneous

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33 Meta-analyser og medfødte misdannelser blandt ART børn Study Year Studies accepted OR (95% CI) Rimm et al ( ) Hansen et al * 1.29 ( ) Wen et al ( ) Hansen et al * 1.32 ( ) *Many studies considered acceptable in the 2005 review by Hansen et al were no longer considered acceptable in their 2013 report

34 Large population-based studies on congenital anomalies in ART pregnancies ( ) Study Years of sample accrual Adjusted OR (95% CI) Statistical significance Country Kallen et al ( ) Yes Sweden Davies et al ( ) Yes Australia (Adelaide) Halliday et al ( ) Yes Australia (Parkville) Hansen et al ( ) Yes Australia (Perth) Pinborg et al ( ) No Denmark Klemetti et al ( ) Yes Finland Ombelet et al ( ) No Belgium Kallen et al ( ) Yes Sweden Kelley-Quon et al ( ) Yes USA (California) Fuji et al ( ) No Japan 34

35 ART Long term outcomes

36 Hazard ratio (95% CI) for cancer in children born after ART vs non-art ART n Non-ART n Crude* Any cancer ( ) Adjusted** 1.15 ( ) *Age at diagnosis and time of follow-up incorporated **Adjustment for country

37 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

38 Diastolic and systolic BP Fat deposits Fasting glucose Fasting insulin, lipids Bone age

39 Paediatric Research_Ph.D.course_29.April 2015_

40 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, (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 (0.90 to 1.15) 0.88 (0.63 to 1.24) 0.98 (0.83 to (0.91 to 1.23) 1.14 (0.56 to 2.29) ICSI (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).

41 Academic performance in ART adolescents aged years National birth cohorts 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, June, Lisbon, Portugal, 2015

42 Academic performance in ART Adolescents aged 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) < *After adjustment for educational level and SES differences disappeared 42

43 ART Key Messages Obstetriske og perinatal outcomes Misdannelsesrisiko Kromosom anomalier (ICSI) 2.0 Cancer risiko er ikke øget Langtidseffekter? Akademiske kundskaber ligner gennemsnittet Perinatale risici er faldet over tid for ART børn

44 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)

45 ART En god historie

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