Achieving Pregnancy Achieving Pregnancy Using Fresh Versus Using Fresh Versus

Cryopreserved Semen for Cryopreserved Semen for Donor InseminationDonor Insemination

Blood Products Advisory Committee, Blood Products Advisory Committee, 12/14/0112/14/01

Emmet J. Lamb, M.D.Emmet J. Lamb, M.D.

Professor of Gyn- Ob, EmeritusProfessor of Gyn- Ob, Emeritus

Stanford University, Stanford, CaliforniaStanford University, Stanford, California

Indications in 2001Indications in 2001for donor insemination for donor insemination

Azoospermia or severe Azoospermia or severe oligospermiaoligospermia ICSI not availableICSI not available

No spermNo sperm Not successfulNot successful Too CostlyToo Costly

Genetic problem of maleGenetic problem of male No male partnerNo male partner

Variables that improve Variables that improve fecundity Stratify in fecundity Stratify in

analysis analysis 1.1. Azoospermic MaleAzoospermic Male

2.2. Young femaleYoung female

3.3. Normal femaleNormal female

4.4. Parous femaleParous female

5.5. Short duration infertilityShort duration infertility

6.6. First cycle First cycle

Variables that can be Variables that can be changed changed

to improve fecundity to improve fecundity

Donor selectionDonor selection FertileFertile High motile High motile

sperm countsperm count Good Good

cryosurvivalcryosurvival Fresh spermFresh sperm CryopreservatiCryopreservati

on Methodson Methods Sperm Sperm

preparationpreparation

Insemination MethodsInsemination Methods Ovulation monitoringOvulation monitoring

Cervical mucus and Cervical mucus and BBTBBT

Urinary LHUrinary LH Pelvic ultrasoundPelvic ultrasound

Ovulation enhancementOvulation enhancement ClomipheneClomiphene GonadotropinsGonadotropins

Comparing FecundityComparing Fecundity

Cycle fecundity Cycle fecundity Total pregnancies / Total cycles of exposureTotal pregnancies / Total cycles of exposure Assumes constant hazard rate.Assumes constant hazard rate.

Easy calculationEasy calculation Easy explanationEasy explanation Close to realityClose to reality

Kaplan Meier survival analysisKaplan Meier survival analysis Cox proportional hazard regression Cox proportional hazard regression

analysisanalysis

Fresh versus thawed semenFresh versus thawed semenMeta-analysis of cycle Meta-analysis of cycle

fecundityfecundity         ThawedThawed FreshFresh OddsOdds

TypeType StudyStudy YearYear Preg.Preg. TotalTotal Preg.Preg. TotalTotal RatioRatio

RR SubakSubak 19921992 99 9696 2121 102102 0.400.40

RR IddendenIddenden 19851985 1313 151151 1010 153153 1.351.35

RR KeelKeel 19891989 4444 917917 1818 310310 0.820.82

RARA BrownBrown 19881988 5959 566566 153153 559559 0.310.31

RARA RichterRichter 19841984 5454 17671767 126126 711711 0.150.15

CC SmithSmith 19811981 3838 500500 121121 613613 0.330.33

CC SchoysmanSchoysman 19801980 415415 20272027 148148 610610 0.800.80

CC BordsonBordson 19861986 1717 165165 1919 165165 0.880.88

CC JacksonJackson 19771977 1919 540540 336336 67606760 0.700.70

CC ChongChong 19851985 5454 176176 7373 290290 1.321.32

HH KossoyKossoy 19891989 1414 110110 4343 445445 1.361.36

HH DimarzoDimarzo 19901990 2121 371371 332332 30403040 0.490.49

HH BartletBartlet 19941994 3232 372372 1818 177177 0.830.83

CDCD LeetonLeeton 19801980 229229 15021502 3636 179179 0.720.72

                       

   Total subjectsTotal subjects 23,37423,374 1,0181,018 9,2609,260 1,4541,454 14,11414,114 0.620.62

Meta-analysisMeta-analysisSummary Statistics Summary Statistics

Total subjectsTotal subjects 23,374 23,374 Summary odds ratioSummary odds ratio 0.62 0.62

(0.43 to 0.90)(0.43 to 0.90) 2p Fresh v. Thaw2p Fresh v. Thaw 0.011 (Z= -0.011 (Z= -

2.55)2.55) Heterogeneity, QHeterogeneity, Q 129 (Tau 129 (Tau

sq= 0.42)sq= 0.42)

Fresh versus Thawed Fresh versus Thawed SemenSemen

Cumulative Meta-analysisCumulative Meta-analysis

Cycle fecundity with donor frozen semen

in clomiphene or unstimulated cycles

O’Brien in Cochrane Library, 2001

Frozen SemenFrozen Semen

Lower fecundity = more cyclesLower fecundity = more cycles More drop-outsMore drop-outs Fewer childrenFewer children Greater use of limited resourcesGreater use of limited resources

More multiple pregnancies if More multiple pregnancies if gonadotropin stimulation used to gonadotropin stimulation used to compensate for lower fecunditycompensate for lower fecundity

The use of frozen The use of frozen semensemen

to avoid HIV to avoid HIV transmission transmission

Stanford University School of Stanford University School of MedicineMedicine

Michael Payne Michael Payne Health Research and PolicyHealth Research and Policy

Douglas OwensDouglas Owens Internal Medicine and HRPInternal Medicine and HRP

Emmet LambEmmet Lamb Gynecology and ObstetricsGynecology and Obstetrics

Methods of studyMethods of study Gauge health benefit in terms of Gauge health benefit in terms of

QALYs gainedQALYs gained Assign quality-adjusted utility to health Assign quality-adjusted utility to health

states states Calculate quality-adjusted life Calculate quality-adjusted life

expectancyexpectancy Discount utilities at 3%Discount utilities at 3%

Gold, et al. Cost-effectiveness in Health and Medicine. Oxford University Press , 1996Gold, et al. Cost-effectiveness in Health and Medicine. Oxford University Press , 1996

Markov modelMarkov model• Events unfold over time at fixed intervals -- Events unfold over time at fixed intervals --

insemination cyclesinsemination cycles

• Cohort of 80,000 women Cohort of 80,000 women • Monthly cycles (insemination) up to 12Monthly cycles (insemination) up to 12• Yearly follow-up for a lifetime Yearly follow-up for a lifetime

• Two treatment optionsTwo treatment options• Frozen semen. Donor screened twice with EIAFrozen semen. Donor screened twice with EIA• Fresh semen. Donor screened once with EIA.Fresh semen. Donor screened once with EIA.

8/21/01 p 1 Insemination Drop out Childless

Pregnancy loss Parent & uninfected child

Pregnant

Parent & uninfected child

HIV phases 1-5 Infected Pregnant & Infected

Parent & infected child HIV phases 1-5 Infected & Childless Pregnancy loss HIV phases 1-5

Dead

Dead

Probability of Transmission Probability of Transmission of HIV-1 by inseminationof HIV-1 by insemination

Product of two elements:Product of two elements: Probability of infection from 1 insemination with Probability of infection from 1 insemination with

an infected donoran infected donor Probability of an infected donorProbability of an infected donor

Sum of two elementsSum of two elements Missed by EIA: Prevalence of HIV X (1-sensitivity) Missed by EIA: Prevalence of HIV X (1-sensitivity)

EIAEIA In window and not “False” Positive : Prevalence of In window and not “False” Positive : Prevalence of

window donors X specificitywindow donors X specificity

Heterosexual Heterosexual transmissiontransmission

Uninfected partners of infected men Per episode risk = 1 in 500 to 1 in 1000

Mastro & Kitayaporn. Aids Research & Human Retroviruses 1998;14 (Suppl 3):S223-7

Royce, Sena, Cates, Cohen. New Engl J Med 1997;336:1072-8

Dates Group PercentageHIV +

Reference

1990-94 Blood donors 0.007, 0.04% Parrish 1995, Glynn 1998

1997 (P) Semen donors 0.05 Used in Payne, et al. CEA

1988-94 General population 0.15, 0.3 Karon 1996, Davis 1998

1996 (P), 1998 (P) STD clinic heterosexual males

1.1, 2.3 Holmberg 1996, Valdessari 1998

1999 (P) Prisoners 2.6 Ruiz 1999

1996 (P), 1998 (P) Homosexual males (MSM)

6 to 18 Holmberg 1996, Valdessari 1998, Katz 1998

1996 (P), 1998 (P) Injection drug users 5 to 20 Holmberg 1996, Valdessari 1998, Garfein 1996

1995 (P) Commercial sex workers 23 Onorato 1995

Valleroy. FDA BPAC, 12/14/01

Payne, Owens, Lamb. In review 2001.

Prevalence of donors Prevalence of donors in the window periodin the window period 50,000 new HIV cases in males50,000 new HIV cases in males

• 35,000 high risk. 35,000 high risk. • 8,750 (25%) escape screen (by self 8,750 (25%) escape screen (by self

selection, history, STD tests)selection, history, STD tests)

• + 8,750 high risk+ 8,750 high risk + 15,000 low risk+ 15,000 low risk = 23,750 infected potential donors= 23,750 infected potential donors

Peterson, et al Peterson, et al Transfusion 1994;34:1721Transfusion 1994;34:1721

CDC HIV/AIDS CDC HIV/AIDS Surveillance Report 1997Surveillance Report 1997

Prevalence of donorsPrevalence of donors in the window period in the window period

23,750 potential donors / 12 months =23,750 potential donors / 12 months =

1,980 per month1,980 per month X 3 months window periodX 3 months window period = 5,940 per year = 5,940 per year

About 1 in 10,000 of the 65 million males of About 1 in 10,000 of the 65 million males of reproductive age -- 0.0091%reproductive age -- 0.0091%

US Department of Census. Statistical Abstract of US Department of Census. Statistical Abstract of United States 1997. Tables 14,169,170United States 1997. Tables 14,169,170

Outcomes if All 80,000 Outcomes if All 80,000 Inseminations Were FreshInseminations Were Fresh

FreshFresh FrozenFrozen Diff.Diff.

Number of live birthsNumber of live births 39,79239,792 31,08431,084 +8,708+8,708

Number of infected Number of infected womenwomen 0.143020.14302 0.000020.00002 0.1430.143

Number of infected Number of infected newbornsnewborns 0.00484160.0048416

0.0000000.00000066 0.0048410.004841

Outcomes if All 80,000 Outcomes if All 80,000 Inseminations Were FreshInseminations Were Fresh

Mean Fresh Frozen Mean Fresh Frozen DifferenceDifference

Number of insemination cycles 3.83Number of insemination cycles 3.83 4.33 4.33 -0.51-0.51Life years after age 30 44.597Life years after age 30 44.597 43.601 43.601 --

0.0040.004Discounted QALYs 21.02 Discounted QALYs 21.02 20.95 20.95

0.070.07

Donor Donor inseminationinsemination

Micromorts from Micromorts from HIV-1HIV-1

FreshFresh ThawedThawed

One CycleOne Cycle 0.50.5 0.000060.00006

Average Average CourseCourse 1.81.8 0.00020.0002

Maximum Maximum (12)(12) 5.65.6 0.00070.0007

Howard RA. Intn J Tech Assessment Health Care 1989;5:357

Annual Risks at HomeAnnual Risks at Home

Event Micromort

1/n/year1 charbroiled steak/week* 0.4 2500000

Drown in tub 1.7 600000

Plane crashes on home 4 250000

Denver versus NYC* 10 100000

1 peanut butter sandwich/day* 10 100000

1 lite bear/day* 20 50000

Lightening strike 111 9000

Accidents at home 118 8500

* Excess Cancer risk Stallings & Paling. Obstet Gynecol 2001;98:345-9

Annual Micromorts at Annual Micromorts at HomeHome

0.0 50.0 100.0 150.0

Steak

Tub

Plane

Denver

PB Sand.

Beer

Lightening

Accidents

Micromorts

OB-Gyn RisksOB-Gyn RisksSurgery Micromorts 1/n

Legal abortion 4 250,000

Tubal sterilization 20 50,000

Pregnancy 50 20,000

Vaginal hysterectomy 222 4,500

Ectopic pregnancy 400 2,500

Abdominal hysterectomy 800 1,250

Puerperal hysterectomy 3030 330

Hysterectomy for cancer 4000 250

Stallings & Paling. Obstet Gynecol 2001;98:345

Micromorts from Gyn Micromorts from Gyn SurgerySurgery

0 200 400 600 800 1000

TAB

Tubal

Pregnancy

Vag. Hyst.

Ectopic

TAH

ConclusionsConclusions

The risk of using fresh semen in donor The risk of using fresh semen in donor insemination is quite small, in the range insemination is quite small, in the range of risks we accept on a daily basis.of risks we accept on a daily basis.

The reward, higher fecundity, is The reward, higher fecundity, is substantial.substantial.

Informed patients may reasonably accept Informed patients may reasonably accept the risk in order to get the reward.the risk in order to get the reward.