achieving pregnancy using fresh versus cryopreserved semen for donor insemination blood products...
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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.
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