In Vitro Fertilization &

Perinatal Morbidity

Improving Outcomes in the 21st Century

Christopher Montville, MD, FACOGBillings Clinic

Reproductive Specialists

Disclosures

Nothing to disclose

Objectives

•Review the historical significance of IVF on multiple gestation

•Discuss the association of IVF with birth weight, congenital

anomalies, and neurodevelopment

•Interpret the impact of single embryo transfer on IVF

outcomes

Epidemiology of Infertility

• Infertility - Inability to conceive in 12 months with regular intercourse

• Fecundability – probability of conception in one menstrual cycle– 0.25 first three months (25%)– 0.11 – 0.15 next 9 months (11-15%)– 0.03 after 12 months (3%)

• 7.3 million women age 15-44 with impaired fertility

12% of women 15-44 years of age

Female age and fertility

• Fertility declines with advancing age– Decline significant 32-35 yrs

• Oocyte quantity and quality– Acceleration of follicular atresia– Chromosome instability

• Fertilization failure• Higher miscarriage rate

– Chromosomal aneuploidy Age 25 35 40

Trisomy 21 1:1340 1:353 1:85

Fertil Steril 2006; 86(Suppl 4):S248-252

<35 35-37 38-40 41-4205

1015202530354045

% of IVF Cycles Resulting in Live Birth& Natural Miscarriage Rates

Live Births

SAB

Age

Perc

enta

ge

https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0

Clomid Ovulation Induction

Age # Pts PR/Cycle PR/Pt >5 cycles<35 983 11.5% 24.2% 18

35-37 422 9.2% 18.5% 3

38-40 265 7.3% 15.1% 4

41-42 81 4.3% 7.4% 0

Dovey 2008

Limitations of Standard Fertility Therapy

• Female age is the most important factor – Decreasing fertility– Increasing miscarriage rates

• Therapies are limited– Number of successful clomid cycles is limited– Risk of higher order multiples with injections

• 40% of triplet and higher order multiples

• Male factor infertility ~40% of all couples– Insemination improves success 1-3%/month

Goal of Fertility Therapy:“Maximize the probability of pregnancy while

minimizing the risk of a multiple gestation”

Fertil Steril 2012;97:825

IVF History

• First IVF Delivery in USA 1981• Improved Success

– Stimulation protocols– Peer Reviewed Data– Advances in Embryology

• Improved access to care• Better utilization of resources• Faster time to pregnancy• Improved oversight and

standards

Louise Brown, First IVF Baby 1978

IVF: Procedures

• Down-regulation of Pituitary/Ovarian axis• FSH/LH gonadotropin stimulation• Ultrasound monitoring, serum markers• Transvaginal oocyte retrieval• Embryo transfer

– Day 3 vs Day 5

ICSI (Intracytoplasmic Sperm Injection)

• Severe male factor– Oligospermia– Teratoospermia– Obstructive Azoospermia

• Epididymal biopsy• Testicular biopsy

– Cryopreserved sperm

• Unexplained Infertility

ART Utilization 2009

146,244 Cycles

45,870 Live births 60,190 Infants

• 1.4 % of US Births in 2009

– 20% of all multiple birth infants

– 34% triplet and higher order multiple births

• 47.3% of infants conceived with ART were multiples

– 3% of infants in general public were multiples

www.cdc.gov/art

Multiple Births

• Majority of twins from natural conception– Ovulation induction/superovulation: 21-32%– ART: 8-16%

• Higher order multiples:– 39-67% OI/SO (multiple follicles)– 2-3 fold increased risk of monozygotic twins

• Risk of multiples with ART– Number of embryos transferred

Fertil Steril 2012;97:825

Complications and Multiple Gestation

• Maternal– Preeclampsia– Gestational Diabetes– Hyperemeis Gravidarum– Placental abnormalities– Cholestasis– Anemia– Pre term birth

• Fetal/Newborn– Neurodevelopment– Fetal growth restriction– Cerebral Palsy– Retinopathy– Pulmonary dysplasia– NEC

Figure 1

Source: Fertility and Sterility 2012; 97:825-834 (DOI:10.1016/j.fertnstert.2011.11.048 )

Copyright © 2012 American Society for Reproductive Medicine Terms and Conditions

Multiple Births Per Delivery

ASRM Guidelines

Single Embryo Transfer

• Is transfer of one embryo a good option?

ChallengesEmbryo Selection Success RatesPatient characteristics Blastocyst culture

Financial

Country Live Birth Singleton Multiple Singleton

Sweden 27.2% 25.6% 5.8% 94.2%

USA 35.4% 24.6% 30.6% 69.4%

Per Embryo Transfer

Per Live Birth

Single Embryo Transfer

University of Iowa– Age <38 (cycles similar: ~2400)– At least 7 2PN embryos after fertilization– No prior failed IVF cycle – At least 1 good quality blastocyst for transfer– Evaluated pregnancy and multiple rates before

and after implementing policy in 2004

Fertil Steril 2011;96:1367–9

Single Embryo Transfer

Comparison: Before and after 2004 Policy• Live birth rate (%): 51.1 vs. 55.9

• Multiple birth (%): 34.8 vs. 17.5

• Single embryo: – Live birth rate: 64.6%– Multiple rate: 3.4%

Fertil Steril 2011;96:1367–9

Multiple Gestation

• Significant implications on maternal/fetal health• Rates of triplets improving

– Twin rates remain too high

• Single embryo transfer has promise– Active patient education is key

• Aggressive Education?

– Who are the optimal candidates?– Success rates and Financial pressures?

Perinatal Complications and ART

ART Outcomes 2009

Outcome

• LBW• VLBW• Preterm• Very PT

Gen Birth

• 8%• 1%• 12.2%• 2%

ART

• 32%• 6%• 33.4%• 6%

MMWR Surveillance Summaries 2012;61:1-23

Low Birth Weight

Higher incidence in IVF Singletons2009 Meta-analysis: 17 Studies

IVF31,032

Spontaneous81,119

PTB RR: 1.84

LBW RR: 1.60

VLBW RR: 2.65

IUGR RR: 1.45

Eur J Obstet Gynecol 2009:146;138

Low Birth Weight: IVF Twins

IVF4385

Spontaneous11,793

PTB RR: 1.23

LBW RR: 1.14

VLBW RR: 1.28

IUGR RR: 1.06*

Low Birth Weight

Etiologies:– Ovarian Stimulation

• Elevated estradiol concentrations• Endometrial development• Effects on implantation

– Embryo Culture• Extended culture

– Fresh vs Frozen embryo transfer• FET assoc with lower odds of LBW

Fertil & Steril 2013;99:303

Low Birth Weight

• Day of embryo transfer– No significant difference between day 3 or Blast

• Number of embryos transferred– Singletons: single or double embryo transfer

• Mean birth wt higher in SET• Increased risk (OR 3.38) of LBW when 2 embryos

• Vanishing Twin Syndrome– Embryonic loss and absorption– 10-30% of IVF singletons from original twin pregnancy– Increased risk of LBW (RR 1.7)

Fertil & Steril 2013;99:303

Congenital Anomalies

• Increase risk in ART children• Sweden 1982-2006 (n=31,850)

– Incidence declined over time

– Of 16,280 infants born 1982-2000• ART: 5.0% malformation rate (4.0% in gen pop)

– Of 15,570 infants born 2001-06• ART: 5.4% malformation rate (4.4% in gen pop)

– Adjusted risk: AOR: 1.15Birth Defects Res 2010;88:137

Congenital Anomalies

• NEJM 2012– 6,163 ART infants (1407 ICSI)– Followed from 20wks GA to 5 years– Crude anomaly rate: 8.3% vs 5.8% in gen pop– AOR: 1.28

• Singletons with no ICSI, AOR: 1.06• No increased risk overall with IVF

NEJM 2012;366:1803

Role of ICSI

• Male infertility: increased chromosomal anomalies• Inherited and de novo mutations in ICSI children• Less common now

– Utilization of ICSI for non-male factor?

• Swedish study: AOR 0.9• NEJM: AOR 1.55

– Inclusion criteria?

NEJM 2012;366:1803

Neurodevelopment

• No Increased Risk:– Autism– CP– Intellectual Disability– Sensory Impairments– Activity Limitations

Fertil Steril 2013; 99:311

Parental Characteristics

• What is the role of underlying infertility?– >12 months to pregnancy associated with LBW, SGA, PTB– Hum Reprod Meta Analysis 2013:

• 17 studies• 19,983 births to infertile couples• 1,249,775 births to fertile couples

Low Birth Weight: AOR 1.34Small for Gestational Age: AOR 1.07Pre term Birth: AOR 1.31

Hum Reprod 2013;28:125

Treatment Anomaly Unadjusted OR Adjusted OR

IVF-Fresh 71/1005 1.25 (0.98-1.59) 1.05 (0.82-1.35)

IVF-Frozen 34/479 1.24 (0.88-1.76) 1.08 (0.76-1.53)

ICSI-Fresh 76/713 1.95 (1.53-2.48) 1.73 (1.35-2.21)

ICSI-Frozen 15/226 1.17 (0.7-1.97) 1.10 (0.65-1.85)

Conception after ART birth

96/1306 1.54 (1.15-2.05) 1.26 (1.01-1.57)

Infertile –no therapy

52/600 1.54 (1.15-2.05) 1.37 (1.02-1.83)

NEJM 2012;366:1803

Parental Characteristics

• Length of subfertility in ART patients– Many >2-5 years of trying

• Older maternal age– Oocyte quality– Maternal health issues

• Severe male factor– Health of the male partner

• Population studies– Significant differences between countries

Improving Outcomes

• Patient education– Effect of age on fertility

• Improving maternal health• Improved evaluation

– Faster referrals• Instituting strict guidelines

– Single embryo transfer• Improved research

Conclusions

• ART can help couples overcome infertility• Multiple gestation and complications

– Not improving fast enough• Congenital anomalies are more common

– Role of maternal health and underlying infertility• Early patient education • Identification of mechanisms needed

Dr. Robert Edwards, Lesley Brown, Louise and Baby Brown