The Relationship Between infertility Treatment and Birth Defects.

Where We Are, Where Do We Want to Go, and How Can We Get There

Michael Davies, MPH, PhD

Professor & Co-Director

Lifecourse and Intergenerational Health Research Group,Research Centre for the Early Origins of Health and Disease

Lifecourse and Intergenerational Health Research Group

Broad research areas

• Optimal conditions for development to birth and beyond

• Reproductive careers• Involuntary infertility & assisted conception• Intergenerational growth and chronic disease

risk

Current research topics related to ART

• Deferred child bearing in Australia and the impact on fertility

• Influence of lifestyle & demographic factors on fertility, age, smoking, obesity

• Safety and effectiveness of ART– Birth defects

• Long term consequences of infertility treatment for patients and offspring– Intergenerational transmission of metabolic risk

What’s safety?

• Safety is the opposite of danger.• However, the perception of danger is subjective.

• Kurchatov Institute, Russian Scientific Center. Translated from Atomnaya Énergiya, Vol. 80, No. 6, pp. 415–420, June, 1996.

Contributors to perceived ‘safety’

• It’s a value judgement

– Value and probability of desired outcome – Value and probability of unwanted outcome – Modifiability– Inevitability– Background level of risk– Future opportunities– Luck/fate

...“The feeling of wanting a child is so huge when you go through IVF, the least of your worries is having a child that might not be perfect”

There are always going to be children born with difficulties ...it is just one of those things.

“This will lead to a deformed nation. It's selfish and irresponsible. People nowadays think of nothing but their own desires.”

“I disagree with the applicants that infertility/subfertility is a public health problem.

ART is an expensive public health burden that reduces the health and well being of previously well women and increases the risk of suboptimal pregnancy outcomes in an already overpopulated world.”

• “The theoretic risks of pregnancy following IVF and ET ...cannot be drawn until a large number of babies are delivered and a long-term follow-up is completed. Initial results from the current small sample are encouraging.”

• Wood C, Trounsen A, et al. Fertil Steril 1982 Jul;38(1):22-9. Clinical features of eight pregnancies resulting from in vitro fertilization and embryo transfer.

http://aviation-safety.net/statistics/period/stats.php?cat=A1

Annual death rate per 1000 total births from maternal mortality in England and Wales (1850-1970) (Registrar General Reports)

WHO Maternal mortality /100,000 live births 2008

Australia, Sweden, Luxemburg 5

Japan, Canada 7

NZ 8

Western Europe 7

Central Europe 13

USA 17

Eastern Europe 32

Oceania 279

South Asia 323

Sub-Sahara Africa 586

www.thelancet.com Published online April 12, 2010 DOI:10.1016/S0140-6736(10)60518-1

‘Most children born after assisted reproduction techniques are healthy’ Bergh 2012

‘Although the large majority of births resulting from assisted conception were free of birth defects...’ Davies et al 2012

... but knowledge is limited to common, immediate outcomes where there is no lag and slow rates of technical innovation

Over 90% of our passengers arrive without death or major disability

National Birth Defects Prevention Study (NBDPS)5008 control infants and 13 586 case infant

Contributors to ‘risk’

• Patient characteristics– Age, obesity, underlying disease

• Treatment strategies– Multiple embryo transfer

• Treatment effects– Treatment modality, IVF vs ICSI, – Cryopreservation– Ovarian stimulation

• Do ART patients and pregnancies carry distinct risks for adverse pregnancy outcomes?

• Is ART associated with an increased risk of birth defects?

• Are the defects of significance?• Do twins carry the same risk as singletons?• Do all ART exposures carry the same risk?• Is any apparent increased risk due to patient or

ART factors?• Is a sibling comparison model feasible?• Is subfertility a risk?• Can any risk be modified?

N Engl J Med 2012. DOI:10.1056/NEJMoa1008095

Wilkinson, R. Published 1820. Based on work of Mathew Flinders published in 1814

Infertility 2 linkage data

Infertility 1 linkage data

Birth defects registry

South Australian perinatal collection

Terminations in SA Matched file in Dept of Health

De-identified master file N=302,811 +ART births 6,163 (1.5%)Birth defect registrations 17,546 (5.8%)

ART clinical data

Cerebral palsy registry

Groupings considered in the analysis • Group 1 - IVF, ICSI, GIFT, FET, OI, IUI, DI• Group 2 - Spontaneous pregnancies

among ART patients• Group 3 – History of infertility on maternity

record• Group 4 - Unexposed to ART, no infertility history

Confounding?

Potential confounders used in the analysis

• Pre-existing hypertension• Pregnancy induced

hypertension• Pre-existing diabetes • Gestational diabetes• Impaired glucose

tolerance• Anaemia • Urinary tract infection• Epilepsy• Asthma

• Maternal age group• Parity• Fetal sex• Gestation• Smoking in pregnancy• Australian Standard

Classification of Occupation (ASCO) with 282 categories

• Year of treatment

INCLUSION LIST EXAMPLESConditions for exclusion are contained in the appendix of the annual reports contained ate the following web site.

http://www.wch.sa.gov.au/services/az/other/phru/documents/2002_sabdr_annual_report.pdf

• CARDIOVASCULAR DEFECTS • (74500 - 74799)• Transposition of Great Vessels • (74510 - 74519) • Tetralogy of Fallot • (74520)• Ventricular Septal Defect • (74540 - 74549) • Atrial Septal Defect • (74551 - 74559) • Hypoplastic Left Heart Syndrome • (74670)• Patent Ductus Arteriosus • (74700) • Coarctation of Aorta • (74710 - 74719)

• URO-GENITAL DEFECTS • (75200 - 75399) • Undescended Testis (treated) • (75250 - 75254, 75257) .• Hypospadias • (75260, 75263 - 75269).• Renal Agenesis or Dysgenesis • (75300 - 75306) .• Cystic Kidney Disease• (75310 - 75319) .

• Obstructive Defects Renal Pelvis • (75320 - 75329) .• Vesico-Ureteric Reflux • (75344) .• Other Anomalies of Ureter • (75340 - 75343, 75345 - 75349) .  

• MUSCULO-SKELETAL DEFECTS • (75400 - 75699) • Developmental Dysplasia of Hip • (75430 - 75434, 75439) .• Talipes • (75450, 75454-75456,75473) .• Polydactyly • (75500 - 75509).• Syndactyly • (75510 - 75519) • Reduction Deformities • Upper and/or Lower Limbs • (75520 - 75549)• Craniosynostosis • (75600, 75601)• Diaphragmatic Hernia • (75661)• Exomphalos • (75670)• Gastroschisis • (75671)

ART and syndromes

Non-significant ART effect on the following syndromes:

• Downs • Edwards • Pataus • Pierre-Robin • Turners • Klinefelters • Angelman • Beckwith-Wiedemann

• Imputing an ART birth defect rate of 8.3% from the Davies et al NEJM paper there has been approximately 415,000 major birth defects from the 5m ART births.

• This would be reduced by 123,125 (29%) to 291,875 if the birth defect rate matched that of the general population.

• This would require addressing treatment, patient, and multiple pregnancy factors – some of which are currently not under technical control.

• Are assisted reproductive technologies (ART) a useful model for the study of endocrine disruptors?

Selective estrogen receptor modulators (SERMs) are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances is that their action is different in various tissues.

Clomphene citrateTamoxifenBisphenol A

Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews

Bower C, Hansen M. Reproduction Fertility and Development, 2005, 17, 329-33.

Risk of adverse perinatal outcomes among singletons by mode of conception, SA, 1986-2002

Donor Oocyte

GIFT ICSI Fresh

ICSI Frozen

IUI IVF Fresh

IVF Frozen

Mini-mal In-terven

Ov. In-duc.

Spon-tan-eous

Infertile Clomiphene at home

Male

-211.32

9

-203.65

4

-207.73

9

64.2908

-110.38

9

-294.80

5

-39.979

2

-21.530

3

-157.71

5

-8.8887

-311.57

1

-559

Fe-male

-170.10

8

-275.43

5

-150.02

1

28.9684

-127.34

2

-228.13

6

-33.348

8

-35.123

1

-8.6078

-52.697

5

-174.22

4

-282

-550

-450

-350

-250

-150

-50

50

Difference in birthweight by ART groups relative to sex specific populations for singletons adjus-

ted for gestation

Gm

s

n/a 10.0* 10.4* 7.8 8.6* 7.3* 6.7 6.1 7.2 7.4* 8.3* 19.4*Major birth defects %unadjusted

*significantly different to fertile population prevalence of 5.7% in fully adjusted model

Programming issues

• Timing, type, magnitude and duration of exposures

• Range of effects• Latency between exposures and outcomes • Critical periods for programming (pre- postnatal)• Interaction or effect modification (environment,

genetic factors)• Maternal health status (body composition)• Transgenerational effects

Range of longer term health and development outcomes

• Higher peripheral body fat deposits, sum of skin folds, fasting serum glucose concentrations, systolic and diastolic blood pressures (Ceelan et al,2007, 2008) (Belva eta l 2012).

• High infancy growth velocity (Ceelen at al 208)• Cancer in children (Kallen et al 2005; 2010)• Cancer in both child and mother after infertility treatment (Hargreave M,

et al 2013)• Hospital admission for asthma beyond the first year of life (Ericson et al

2002).• Prescription for asthma medication (Kallen et al, 2013)• Subclinical hypothyroidism (Sakka et al, 2009).• Increased contact with disability services (Pinborg, 2005)• Autism spectrum disorders (Baye, 2013; Hvidtjorn 2009)

Potential extension studies

• Add further years of data • Replicate in other locations & develop

metaanalyses• Long term follow-up of physical, metabolic, social

and intellectual development in ART offspring• Link to child and youth health, PBS, disability

services• Link to cancer registries for children and parents• Develop predictive models and collaborate on

mechanistic studies

He that will not apply new remedies, must expect new evils

Francis Bacon

(1561 - 1626)

Supported by grants from the National Health and MedicalResearch Council (349475, 349548, 453556, and 465455) and theAustralian Research Council (FT100101018).We thank Flinders Reproductive Medicine and Repromed inAdelaide for providing clinical data.

Prof Van Steirteghem told the annual meeting of the American Association for the Advancement of Science in San Diego, California:

"I have noticed from the beginning that several clinics use ICSI for everyone. We have to see what will come out in the future, and long term follow up is extremely important, but yes, ICSI has been overused."