Fertility treatments and multiple pregnancy

Professor Cindy Farquhar Fertility Plus National Women’s Health

University of Auckland

fertility P L U STe Ko r i to

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Outline

Multiple pregnancy and fertility treatments Single embryo transfer Fertility tourism

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Fertility

1 in 6 women/couples experience delay in conceiving

‘vulnerable population’ as they often feel pressured by their age, family, time etc

Fertility treatments are not that effective…. Live birth rates per fresh transfer on average -20% or

lower

‘inconceivable” is on TVNZ tonight “So once you are pregnant everything is going to

be okay…..”

fertility P L U STe Ko r i to

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Mulitple pregnancies and fertility treatments

1st IVF baby 1978 1st NZ IVF baby 1983 By 1990s most IVF

clinics reported MP rates of 20-30%

History Multiple births in England & Wales

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100

200

300

400

500

600

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800

900

1000

Twins

Triplets

1st IVF birth

per 100,000 births

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PMMRC multiple pregnancies 2014 5

Twin pregnancy, chorionicity and perinatal loss 2007-2014

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Perinatal related mortality and multiple pregnancies 2007-2014

Significant increase in PNRM from 2007-2014 but no increase from 2011

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Fertility Rx and multiple pregnancies 2007-2014

Caveat: data relies on self disclosure of fertility treatment Over 8 years, estimate 6000 births from IVF/other Rx so 4% of pregnancies from fertility treatments have a perinatal related death

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Perinatal death after fertility treatment

8-year national cohort study of PMMRC in New Zealand of contributory factors and potential avoidability

Limitations – no data on the number of embryos

transferred, mostly relied on self disclosure of fertility treatment

Acknowledgements: Dr Selma Mourad from the Netherlands

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Perinatal deaths following fertility Rx 2007-2014

• 36% of deaths were in women with multiple pregnancies • 71% following IVF (6% ovum donation), 22% following

clomiphene and 6% IUI • Amongst multiple pregnancies, 75% were from IVF

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PSANZ cause of death amongst babies born following fertility Rx 2007 -2014 (n=261)

PSANZ - PDC Total Singleton Multiple congenital abnormality 64 (26%) 48 (28.5%) 16 (17.2%)

perinatal infection 9 (3.4%) 9 (5.3%) 0 (0%)

hypertension 15 (5.7%) 11 (6.5%) 4 (4.3%)

antepartum haemorrhage 27 (10.3%) 18 10.7%) 9 (9.6%)

maternal conditions 4 (1.5%) 4 (2.3%) 0 (0%)

specific perinatal conditions 63 (24.1%) 22 (13%) 41 (44%)

hypoxic peripartum death 5 (1.9%) 4 (2.3%) 1 (1.0%)

fetal growth restriction 20 (7.6%) 15 (8.9%) 5 (5.3%)

spontaneous preterm 40 (15.3%) 23 (13.6%) 17 (18.2%)

unexplained antepartum death 23 (8.8%) 14 (8.3%) 9 (9.6%)

no obstetric antecedent 0 (0%) 0 (0%) 0 (0%)

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PDC Specific perinatal conditions following fertility treatment

Total Singleton Multiple specific perinatal conditions 63 (24.1%) 22 (13%) 41 (44%)

twin-twin transfusion 13 (21%) 0 13 (21%)

Fetomaternal haemorrhage 3 (5%) 3 (5%) 0

antepartum cord complications 4 (6%) 4 (6%) 0

Uterine abnormality/Cx incompetence 19 (30%) 13 (21%) 6 (9%)

Idiopathic hydrops 1 (0.3%) 1 (0.3%) 0 (%)

after reduction procedure 9 (3.4%) 0 9 (9.6%)

following maternal laparotomy 2 (0.7%) 0 2 (0.2%)

birth trauma 1(0.3%) 1 (0.5%) 0

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Perinatal deaths: impact of fertility Rx compared with non fertility

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15

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Congenitalabnormality

Perinatalinfection

Hypertension Antepartumhaemorrhage

Maternalconditions

Specificperinatalconditions

Hypoxicperipartum

death

Fetal growthrestriction

Spontaneouspreterm

Unexplainedantepartum

No obstetricantecedent

% of singletons, not fertility

% of singletons, fertility

% of multiples, not fertility

% of multiples, fertility

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Contributory factors & potential avoidability

Subcohort of fertility babies 2009- 2014, 196 deaths In 33 cases (17%) with contributory factors

16 singletons, 17 multiples Main CF ‘personnel’ and ‘organisation &management of

care’ 21 cases (11%) considered potentially avoidable

For 7 pregnancies, this avoidability was related to fertility Rx and high-order multiples

However…majority of multiples from fertility Rx are potentially avoidable if the single embryo transfer policy applied (approximately 70 births from 2007-2014)

For non-fertility deaths from a comparable cohort this was 27 % CF and 17% PA (both <p0.05)

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Other differences between populations (fertility vs non-fertility)

Fertility patients Significant lower BMI Significantly older maternal age Significantly less deprived Significant differences in ethnicity: fertility patients

are mostly from NZE group (62% of cases)

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PMMRC recommendations

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The move to single embryo transfer

Initially 3-4 embryos were replaced From mid to late 1990s mostly only 2 embryos

replaced in NZ and the rest were frozen In NZ from 2005 single embryo transfer for women

under 37 years old in exchange for two cycles of IVF 50% of cycles are funded so limited control over

private cycles

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Barriers to limiting the number of embryos transferred

Concern that the overall pregnancy rates will fall.......

But taking into account the frozen embryos in pregnancy outcomes has assisted the transition

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The tradeoffs

Cochrane review of 5 trials Transfer 2 embryos:

43% live birth rate and a 29% multiple pregnancy rate

OR Transfer 1 fresh embryo and then 1 frozen embryo:

38% live birth rate and 1% multiple pregnancy rates

Pandian Z, et al. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2013, Issue 7.

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Sweden 1997-2003 IVF/ICSI - All ages

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SET, clinical pregnancy and multiple delivery 2003-2007 Australia and New Zealand

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Percent

Year

Multiple delivery rate

Proportion single embryotransferClinical pregnancy per initiatedcycle

SET introduced

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Deliveries by number of embryos transferred Australia and NZ - 2013

Source: ANZARD 2013

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NZ data for single embryo transfer

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10

20

30

40

50

60

70

80

90

100

Aus NZ Aus NZ Aus NZ

Per cent

2010 2011 2012 2013

< 35 years 35 - 39 years ≥ 40 years

Source: ANZARD unpublished data

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Fertility PLUS at NWH Twin pregnancy rate 2004-2008

2004 2005 2006 2007 2008 2009

2010

2011

2012

2013

2014 2015

% 20 12.5 9.6 10 5 9.5 11 7.1 4.4 2.9 5.9 0.8

Source: NWH ACR

In 2015 at Fertility PLUS, 98% were single embryo transfers, only 2 twin pregnancies and they both occurred in single embryo transfers

SET

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NWH multiple pregnancy rates 2000-2013

Limitations of data: not by DHB of residence

*Audit of MP in 2000 – 6 of the 11 set of triplets were fertility treatment

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Multiple pregnancies in NZ 1998-2014

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2.2

2.4

2.6

2.8

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3.2

3.4

3.6

3.8

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1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Percentage of babies born as multiple births

Source: MOH Maternity and PMMRC reports

Estimate that the MP per birth should be 2%

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So why are our national rate of multiple pregnancies still higher than expected

Older mothers Demographic changes Fertility tourism

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Fertility tourism or Cross-Border Reproductive Care (CBRC)

“…..refers to the phenomenon where infertile patients or collaborators (such as egg donors or potential surrogates) cross international borders in order to obtain or provide reproductive treatment outside their home country”

Today – focusing on international ART Not covering international surrogacy

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Cross-Border Reproductive Care

Global “hubs” of CBRC

Spain → oocyte donation Denmark → sperm donation India → commercial gestational surrogacy China South America United States Thailand

Emergence of CBRC “Brokers”

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Why do NZ couples choose fertility Rx abroad?

Regulatory, legal or ethical restrictions on treatment Prohibitions on sex selection Age limitations for donor ovum Desire for anonymous gamete donors

Other considerations Availability of gametes Waiting times, especially those caused by a shortage of

gamete donors Ability to have treatment in a culturally and linguistically

familiar country Lower cost

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Implications of CBRC – our patients

Advantages Patient autonomy and fits with the principle of freedom

of movement Access to treatment is faster

Concerns Added practicalities of travel/costs to the difficulties

and stress of undertaking ART treatment Lack of counselling offered by cross-border clinics Potentially differing levels of safety and quality in some

clinics outside “home” jurisdictions; fragmented care

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Implications of CBRC – Resulting Children

No empirical evidence yet on experiences of

individuals born as a consequence of CBRC Need to adequately consider the rights and

interests of children especially when a third party is involved

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Implications of CBRC - “Home” Country Health Care Systems

Increased multiple pregnancy lack of restrictions on number of embryos

transferred means MP the resulting increased health risks and costs

22% of high order multiple births in a London-based multiple pregnancy clinic between 1996-2007 had CBRC

McKelvey 2009

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Implications of CBRC - “Home” Country Health Care Systems

Other complications e.g. OHSS, heterotopic pregnancy etc Who manages and pays for any complications of

treatment? Lack of documentation/communication with the treating

clinic makes diagnosis of complications more difficult Doctors/clinics in the home country may be reluctant to

see the patient for follow up after a procedure performed abroad

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HART Act 2004 Principles

a) the health and well-being of children born as a result of the performance of an assisted reproductive procedure or an established procedure should be an important consideration in all decisions about that procedure:

b) the human health, safety, and dignity of present and future generations should be preserved and promoted:

c) while all persons are affected by assisted reproductive procedures and established procedures, women, more than men, are directly and significantly affected by their application, and the health and well-being of women must be protected in the use of these procedures:

d) no assisted reproductive procedure should be performed on an individual and no human reproductive research should be conducted on an individual unless the individual has made an informed choice and given informed consent:

e) donor offspring should be made aware of their genetic origins and be able to access information about those origins:

f) the needs, values, and beliefs of Māori should be considered and treated with respect:

g) the different ethical, spiritual, and cultural perspectives in society should be considered and treated with respect.

• health and well-being of children….important consideration

• health and well-being of women must be protected • informed consent • donor offspring should be made aware of their

genetic origins • needs, values, and beliefs of Māori should be

considered

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HART Act 2004

Established Procedures

• Artificial insemination • Assisted hatching • Blastocyst culture • Collection of eggs/sperm

for purposes of donation • Sperm, ooctye, embryo,

ovarian tissue cryopreservation

• GIFT • ICSI • IVF • PGD

Requiring Ethical Approval

• Surrogacy • Embryo donation • Donation of gametes

between certain family members

• Creation and use of embryos created from donor eggs and donor sperm

Prohibited Actions

• Creation or use of cloned or hybrid embryos

• Obtain or use gametes from a minor (<16 year old)

• Commercial supply of gametes or embryos

• Commercial surrogacy • Storage of

embryos/gametes for >10 years without specific ethical approval

• Gender selection unless to prevent a genetic disorder/disease

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Summary

The rise in perinatal deaths from multiple pregnancy was mostly due to increase inTOP and neonatal deaths

The proprotion of multiple pregnancies from fertility treatment in NZ clinics are low compared to international figures

Fertility tourism is a widespread growing phenomenon but the numbers are unknown and it is difficult to control

Our current legislation and guidelines in NZ protect donor and offspring

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Acknowledgements

Vicki Masson Lynn Sadler Dr Selma Mourad Dr Karen Buckingham

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