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Fertilitet , infertilitet og assisteret reproduktion i et overordnet perspektiv. Anders Nyboe Andersen Professor dr med, Fertilitetsklinikken , Rigshospitalet U- kursus i Infertilitet , Odense 2014. Infertilitet Ikke et nyt problem – men nye behandlinger.

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Fertilitet , infertilitet og assisteret reproduktion i et overordnet perspektiv

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Fertilitet, infertilitetogassisteretreproduktioni et overordnetperspektiv

Anders Nyboe Andersen

Professor dr med, Fertilitetsklinikken, Rigshospitalet

U-kursusiInfertilitet, Odense 2014

InfertilitetIkke et nyt problem – men nyebehandlinger

In “marriages which had lasted five years or more, and in which the husbands were under 75 years of age, ... one marriage in 6·5 was unproductive".

J Y Simpson

Survey of 495 British Peers, cited in Gibbons (1911)

Den humane forplantning

  • De frivilligt frugtbare fødslerne

  • De frivilligt ufrugtbare svangerskabsforebyggelse

  • De ufrivilligt frugtbare provokerede aborter

  • De ufrivilligt ufrugtbareinfertilitet

Sex og reproduktion

  • 1960’erneSex uden reproduktion

  • 1990’erneReproduktion uden sex

Da jeg blev født i 1948…..

de store efterkrigsårgangeop

Antalbørnfødti Denmark


Fri abort

Små fødselsårgange giver små fødselsårgange

Reproductive health

”Reproductive health is a state of complete physical, mental and social well-being and not merely the abscence of disease or infirmity, in all matters relating to the reproductive system and to its function and processes. Reproductive health therefore implies that people are able to have a satisfying and safe sex life and that they have the capability to reproduce and the freedom to decide if, when and how often to do so”.

United Nations, 1995, p. 40

European Parliament Report

G. ”Infertility is one of the causes of demographicdecline and it shouldberecognised as a public-healthconcern and as a social problem affectingboth men and women”

26. ”Notes thatinfertility is a medicalconditionrecognised by WHO thatcan have severeeffectssuch as depression; points out thatinfertilitymaybeon the increase …; callson the Member States to ensure the right of couples to guarantee universal access to infertilitytreatment and medicallyassistedprocreation by taking steps with a view to reducing the financial and otherobstacles”

European Parliament. Reporton the demographic future of Europe. (2007/2156(INI)), 30th January 2008

ART and fertility treatments From scepticism to acceptance to promotion

  • European Parliament report on the demographic future of Europe (2008):

  • “... calls on the Member States to ensure the right of couples to guarantee universal access to infertility treatment and medically assisted procreation by taking steps with a view to reducing the financial and other obstacles.”

OECD: The Role of Policies, 2005; Report 2007/2156(INI) 2008.

I. Definitioner

  • Infertilitet og subfertilitet defineres som > 12 mdrs. forsøg på at opnå graviditet.

  • Primær og sekundær infertilitet.

Pregnancies in fertile and subfertile couples

Bongaards JA. A method for estimation of fecundability. Demography 1975; 12, 645-60.

Definitioner af infertilitet


Kvinden har aldrig opnået graviditet trods mindst 12 måneders ubeskyttet sexuelt samliv


Kvinden har tidligere været gravid med har efterfølgende ikke opnået graviditet trods mindst 12 måneders ubeskyttet sexuelt samliv

WHO, 1993

Sterilitet anvendes ved definitivt ophævet graviditetsmulighed (hysterektomi, bilateralt salpingectomi, azoospermi)


Prævalenser blandt deltagere, der har forsøgt at få mindst et barn

Livstidsprævalensen af infertilitet > 1 år17-26%

Livstidsprævalensen af infertilitet > 2 år12-14%

Primær ufrivillig barnløshed (infekunditet) 3-8%

Sek. ufrivillig barnløshed (infekunditet) 4-6%

Andel infertile, der har søgt læge50-80%


  • Fertilitet eller fekunditet betyder frugtbarhed og anvendes både om evnen til at opnå graviditet og om evnen til at opnå fødsel af levende barn.

  • Fertilitet eller fekunditet kvantiteres som den månedlige chance for graviditet/fødsel efter ubeskyttet samliv ( fx 0.25 eller 25%).

  • Time to pregnancy (TTP) er et følsomt mål for fertiliteten/fekunditeten og angives som antallet måneders ubeskyttet samliv før graviditet opstår

Fecundity according to age

Live births per cycle

Couples: 544

Children: 3,846


Amenorrhea: 10 months

Children/woman: 10,8

Larsen U et al. Social Biology 2000; 47: 34-50

Donor IUI. Pregnancies/100 cycles

6,139 IUI-D cycles

1,001 treated women

All during 18 years


Botchan A et al. Hum Reprod 2001; 16: 2298-2304

Age related chances of pregnancy over time.

Natural conception

Adapted from H. Leridon (2004) and

D. Habbema

Pregnancy and live-birth rates after ART in relation to age. USA 2005

Fertiliteten falder med alderen – det ovarielle ur

Broekmans et al,

Trends in Endocrinologi & Metabolism, 2007

Oligo-follikulære, lille,

follikel depleterede


Multifollikulære, store

”unge” ovarium

AFC = 34

AMH = 51 nmol/l

AFC = 2

AMH < 3 nmol/l

Total Fertility rate

Total fertilitets rate er antallet af levende-fødte børn per kvinde, efter afslutning af hendes reproduktive periode (typisk udgangen af 49 år).

Total fertility rate er sammensat af biologiske, medicinske og samfundsmæssige forhold.


Total fertility rate


Childness women due to infertility (UK data)

  • A cohort of 40-55 årige ( n=6584)

  • Involuntarilyneverpregnant and thusneverdelivered 2.4%

  • Involuntarilyneverdelivered, althoughachievedpregnancy 1.9%

    SUM: 4.5% unresolvedinfertility

    Oakley et al. Lifetimeoprevalence of infertility and infertilitytreatment in the UK. Hum Reprod. 2008; 23, 447-50.

II. Ændringen i fertilitetsmønstret

Fertility desires in Europe

Federal Institute for Population Research; DIALOG (http://www.bosch-stiftung.de/content/language1/downloads/PPAS_en.pdf). The Demographic Future of Europe – Facts, Figures, Policies. Results of the Population Policy Acceptance Study (PPAS)

Slide from

Mark Connolly

Fertility desires in different countries

  • In some countries the desired number of children would be 3-4.

  • In other countries the desired number would include delivery of a boy.

Kvindens alder vedførstefødselDenmark 1965-2012

Danmarks Statistik Online: www.dst.dk

Age 1 child in Spain

  • Mean age at first pregnancy (INE 2011)

32.1 years

From Data Juan-C Velasque (Spanish Institute of statistics www.ine.es)

Number of children – by age of the firstchild

Antalbørnog alder vedførste barn

Birth cohort


Birth cohort


Infertile couples


Why is female age and delayedchildbearing so important?

  • Lowerfecundity (lesspregnancies - more miscarriages) with age.

  • Accumulatedrisks of

    • reproductivediseases

      • endometriosis

    • diseaseswithreproductiveconsequences.

      • sexuallytransmitteddiseases, fibroids, gastrointestinalsurgery

    • sum of lifestyle factors

      • obesity, smoking

III. Causes of infertility

Causes of infertility (n=4972)

Female age

Diagnosis< 35 > 35

Ovulatory dysfunction24%11%

Endometriosis5% 3%

Tubal factor18%25%


Male factor35%33%

Maheshwari, Hamilton and Bhattacharya. Hum Reprod, 208; 23,538-42

Worldwide patterns of infertility: is Africa different?

WHO task force on diagnosis and treatmnent of infertility. Lancet, 1985, sept. 14. 596-8

Analysis of prospective, standardised data from

42 countries.

Secondary infertility (16 – 40%) Africa 52%

Total tubal occlusion (11–20%) Africa 49%

Is infertility increasing? life-time prevalence

4466 women, 2007. Scotland.

400 (9%) did not wantchildren

4066 wishedchildren

3283 (81%) conceivedwithin 12 month

783 (19%) experiencedinfertility (prim, sec, both)

550 (70%) soughtmedicaladvice

320 (58%) conceived

230 (29%) remainedinvolutarilychildless

Comparedwith a similarsurvey in the same geographical

area 20 yearsago, the prevalence of infertilitywaslower

Bhattacharya et al. Hum Reprod, 24, 12, 3096-3107.

Templeton et al. BMJ, 1990,301, 148-152

Treatment of infertilityAssisted Reproductive Technology ART

The ideal demands for a “successful” Health Technology (ART)






Development of recorded ART cycles in Europe

Data from ESHRE’s EIM consortium

Development of recorded ART cycles in the United States

Data from CDC

Expansion of ART Cycles in Japan


FER: Frozen & Thawed Embryo Replacement

JSOG data

ART and IUI in Denmark, 2012The contribution to annualbirths – an estimate

In women > 35 years 10 - 18% of all Danishdeliveries in 2011 were due to ART

Danish National ART Registry

IVF,ICSI, FER and ED in Denmark1994 - 2010

TreatmentsPregnancies, % Embryos





2006 9.93626.1

2005 9.54123.81

2004 9.59826.7

2003 9.29226.9

2002 9.65025.2

2001 8.80524.5

2000 8.28224.5 2

1999 7.62424.9

1998 7.28124.0

1997 6.76823.3

1996 4.76324.5

1995 4.28523.0 3

1994 3.48020.6


ART cycles / million in Europe, 2006(Countries with complete recording)

France, UK, Germany

ESHRE EIM, Data from 2006, Amsterdam July 2009.

ART cycles / million in selected countries around the world,2002


ICMART World Report, 2002. Hum Reprod, 2009, 24, 2310

Is ART accessible in Montana or Wyoming ?



ART cycles / million in different states United States

ART cycles in Massachusetts

In Wyoming

Wright et al. Surveillance Summaries, 2006, 55, SS-4

Use of ART

The conclusion:

ART is increasingly used around the world – but the technology may not be equaly available for all those who need it – the infertile couples?

Denmark: 21 Fertility Clinics

9 public, 12 private

Cycles per million inhabitants








Conclusion II

  • The use of ART defined as the number of treatments per mio. inhabitants shows a marked variabilitybetweencountries

  • Up to 5-fold differences areseenalsobetweencountrieswithsimilardevelopment and wealth (GNP).

  • Marked local (urban vs. rural) variations alsoseems to exist and this is related to (caused by?) delayedchildbearingduringurbanisation.

Part II. What is the real need for ART?

The ideal equilibrium:

Patients have access to and use treatments to such an

extend that it will meet their demands.

The question:Would the demands be similar in different countries?

How many cycles per year would it take to meet the demands?

What is the real need for fertility treatments in terms of number of cycles?

International estimates of infertility prevalence and treatment-seeking:

potential need and demand for infertility medical care

Jacky Boivin1,4, Laura Bunting1, John A. Collins2 and

Karl G. Nygren3 . Hum. Reprod, 2007, 22, 1506

The need for infertility treatment

Current prevalence of infertility, 12 month definition (25 surveys)

More developed nations4 – 17%

Less developed nations7 – 9 %

Overall mean of 9.0%

Seeking of Medical care (17 surveys)

More developed nations56 (42 – 76%)Less developed nations51 (27 – 74%)

Main conclusion

Great similarity between countries and regions of the world

Jacky Boivin1,4, Laura Bunting1, John A. Collins2 and Karl G. Nygren3 . Hum. Reprod, June 6th, 2007

The potential need for ARTData for developed countries. (those countries that could afford it)

Reproductive age group

Number of women aged 20–44 years who are in a marital

or consensual union122 039 123

Potential need (current prevalence of infertility)

Number of women 20–44 years in marital or consensual union

currently not conceiving in 1 year (while not using a

contraceptive method). Estimate (9%) 10 983 521

Demand for treatment.

Number of infertile couples seeking medical care.

Estimate (56%) 6 150 771

Boivin J et al. Hum Reprod, June 6th, 2007

The potential need for fertility treatments

Our ”target group” is 9% of females in the reproductive age groups (in our part of the world)

The 56% of those couples that seek medical care correspond to 6 million couples annually in the most developed part of the world – and 5-6 times more in the rest of the world.

Impact and the necessary number of treatments / million

Collins and Steirteghem. Overall prognosis with current

treatment of infertility. Hum Reprod Update, 2004, 10,309-16.

Conclusion III Potential need for ART

Average current National use of ART is much

below the optimal (5-8.000 cycles/mio)

needed if all eligible couples should be

given the full benefits of ART.

Part IV: Causes of inequalities in availability ART

  • Relevant therapy not legal in specific countries

    Consequence: law evasion – cross border reproductive care

  • Not affordable for many – lack of re-imbursement through National Health Programs or compulsary insurances.

    Consequence: Socio-economic inequalities

  • Technology not acceptable for some – do not start or drop-out before completion of an appropriate number of cycles

    Consequence: Lower use, higher drop-out and loss of pregnancies

Chambers GM et al: Fertil Steril 91:2281-94, 2009


Conclusion VEconomic factors are important

  • Re-imbursement is clearly related to the ART activity

  • There seems to be an inverse relation between a high activity and the cost per cycle

The overall use of ART

  • The currentprevalence of infertility, linked to delayedchildbearing

  • The ”threshold for treatment” ( Threshold by professionals and patients)

  • Couplesacceptance to undergo ART

    Their perceptions of the benefits (delivery rates) risks, inconvenience and ”cost” of ART.

  • Couplesacceptance of repetitivecycles(drop-out problem)

Couples acceptance of ART

  • Should be efficaciousDelivery rates

  • The risks OHSS

    Ovarian cancer


  • Should be accessibleFinance


  • The burden of doing itvisits to clinic

    bloodtests, oocyte retrieval


Threshold to refer to ART by the doctors


Ease of referral

Professional guidelines

Political criterias for referral

(Who ”qualify for ART”)

Let me propose that…..

  • ART is more accessible and used in those European countries that have the following profile

    ART is considered a simple treatment

    Low-dose protocols

    Low cost

    Single embryo transfer

    NHS ART - a sign of acceptance from society – not just economy

    Regulated and monitored by society – this cause trust and confidence in ART

Conclusion VI. What to do in order to make ART equally available for all who need it? (Real success of ART)

As professionals we need to be active in political decision making as well as among professional colleaques to make ART accessible, affordable and acceptable for those who need it, by:

  • Incorporation of ART programs into National Health Programs – emphasize the population aspect (European and Korean examples)

  • Make clinics geographically available around the country

  • Reduce the costs in private and public clinics

  • Reduce stress / burden and inappropriate restrictions to enter ART programs

  • Reduce stress / burden and thus drop-out during their course of treatments

Thank you for your attention

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