Download College of Physicians and Surgeons

United States Clinical Experience with
Assisted Reproductive Technology in HIVdiscordant Couples
Mark V. Sauer, MD
Professor Department of Obstetrics & Gynecology
Columbia University
New York, New York
Scope of the Problem
 Nearly one million Americans are infected with HIV
 Most HIV-seropositive individuals are of reproductive age
 Heterosexual contact greatest risk factor in women
 Many infected men and women desire to have biologic offspring
 “Safe sex” recommended for prevention, but also prevents pregnancy
CDC. HIV/AIDS Surveillance Report 2003
Family Planning Perspectives 2001; 33:144-152.
Changing Attitude and Outlook
 HAART enhances longevity and quality of life
Compliant patients remain healthy for many years following diagnosis
Disease now considered a chronic illness rather than terminal disease
 Improved awareness of epidemic
 Increased social acceptance
 Emphasis on maintaining productive “normal” lives of infected patients
Hurdles to Fertility Care
 Lack of meaningful published reports defining safety
 No RCTs regarding methodology, safety or efficacy
 No short or long term follow-up of children or families
 CDC recommendation against treatment
 State laws that assign criminal penalties
 Insurance contracts may preclude HIV-seropositive patients
 Perceived liabilities of engaging in care
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Malpractice
Discrimination lawsuits vs conscientious objectors
Patient concerns regarding cross-contamination
Civil and criminal penalties
Clinical and Basic Science Support
 Clinical science: large series reports attesting to general safety
 Over 3,000 washed insemination cycles reported without infection
 Nearly 1,000 IVF cycles reported without infection
 Basic science: defining relationship of virus to reproductive tract tissues
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Transmission through cellular elements in semen or free virus in fluids
Viral cultures of semen commonly positive (10-20%)
Compartmentalization in reproductive tract tissues may occur
Sperm lack CD4 receptor and may not harbor virus
 HIV rarely if ever detected from the most motile washed fraction used in ART
 Sperm surface membrane may allow alternative pathway for HIV gp120 binding
(GalAAG pathway) but remains unsubstantiated
Reprod Biomed Online 2005; 10:135-140.
Programs Reportedly Accepting HIV Infected Patients
 Columbia University, New York, NY
 Eastern Virginia Medical College, Norfolk, VA
 Albert Einstein Medical College, Bronx, NY
 Washington University, St. Louis, MO
 University of Colorado, Denver, CO
 UMDNJ-New Jersey Medical Center, Newark, NJ
Published Clinical U.S. Experience
 Abstracts presented at scientific meetings
 3 of 822 abstracts at ASRM related to HIV in 2002
 4 of 913 abstracts at ASRM related to HIV in 2004
 Peer reviewed CU manuscripts since 2002
 13 papers in print
 2 papers in press
Applying Essential Principles of Medical Ethics
 Autonomy
 Informed rationale decisions
 Alternatives to treatment offered
 Individuals may participate or withdraw
 Non-maleficence
 No evidence of needless harm
 Harm may result from “omission” of care
 Beneficence
 Protects women and children
 Enhances quality of life
 Justice
 Fair distribution of accessible services
Am. J. Bioethics 2003; 3:33-40.
Columbia University Experience
 Consultants providing interdisciplinary support
 Dr. Mark Sauer- Reproductive Endocrinology
 Dr. Scott Hammer- Infectious Disease
 Dr. Jane Pitt- Infectious Disease
 Dr. Shreedhar Gaddipatti- Maternal Fetal Medicine
 Dr. Kenneth Prager- Medical Ethics
 Initiation of fertility treatment of HIV-seropositive males 1997
 Initiation of fertility treatment of HIV-seropositive females 2002
Columbia University IVF/ICSI Program Goals
 To provide HIV serodiscordant couples an opportunity to safely have a child
through assisted reproduction using IVF/ICSI
 Access to a common procedure available throughout the U.S.
 Provide a therapy that doesn’t cross legal boundries of “insemination”
 Decrease the time to pregnancy, and number of needed exposures by ART
 To gather data to further understand the needs of HIV seropositive patients
seeking fertility assistance
 Social, demographic, medical and reproductive database
 Follow up of families and individuals treated
 To report ongoing experience to patients and professional peers in hope of
changing attitudes and reducing prejudice
 Encourage development of new programs
 Seek professional collaboration within REI and other disciplines
Columbia University Experience
 Enrollment Criteria
 Men under active medical care and surveillance
 Demonstration of stable viral loads and CD4 status
 Individuals with viral counts > 30K cps/mL required to begin HAART
 Semen analysis with a total motile count > 1,000,000
 Female partners reproductively competent to undergo IVF therapy
 COH using standard GnRH-analogues and injectable gonadotropins
 Cycle monitoring using serial transvaginal ultrasound and serum E2 levels
 Egg retrieval under anesthesia by transvaginal ultrasound guided needle aspiration
 Transcervical embryo transfer on day 3 or day 5 post aspiration
Columbia University Experience
 Laboratory: Sperm Processing and IVF-ICSI
 Fresh samples with 2 day abstinence
 Class II biologic hood outside embryology lab for processing
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Double wash technique following centrifugation with discontinuous density gradient
45-60 minute swim up
Only most motile fraction selected for ICSI
ICSI 4-6 hours post aspiration
Separate incubators
 ETs days 3 or 5
 Cryopreserve extra embryos
 Separate cryotanks
Post-transfer Surveillance
 Serum pregnancy test 12 days post ET
 HIV-RNA testing each trimester in pregnant patients and at delivery and 3
months postpartum
 HIV-RNA or HIV-DNA tests at delivery and 3 months in newborns
 Non-pregnant patients tested with HIV-EIA or HIV-RNA 3 and 6 months postembryo transfer
Published Early Experience
 Couples treated
61
 Initiated cycles
113
 Retrievals performed
100 (88.5%)
 Clinical pregnancy rate per ET
44.8%
 Delivery rate per ET
36.5%
 Delivery rate per couple (inc. fresh and frozen ET)
54.1%
 Seroconversions in treated patients
0
 Seropositive newborns
0
Am J Obstet Gynecol 2002; 186:627-633.
Fertil Steril 2003; 80:356-362.
Columbia University Results
 195 couples evaluated from 1998-2005
 178 male HIV-seropositive
 12 female HIV-seropositive
 5 both partners HIV-seropositive
 150 couples accepted into care
 135 HIV-seropositive male
 12 HIV-seropositive female
 3 both partners HIV-seropositive
 Variety of referral
 50% from infectious disease specialist
 35% self referred through internet or friends
 15% from obstetrics/gynecology
 Increasing number of cases with increased knowledge of availability
 1997-2002 total of 50 cycles initiated of IVF-ICSI
 2002-2005 total of 189 cycles initiated of IVF-ICSI
Columbia University Results
Male HIV Discordant Experience, 1997-2005
Initial Patient Consultations
n=178
f/u Pending
n=43
f/u Initiated
n=135
Total Cycles Initiated
n=274
IVF-ICSI
n=239
Donor
n=8
Transfer
n=8
Liveborn
n=3
FET
n=35
Nondonor
n=231
Cancelled
n=22
Liveborn
n=13
Retrieval
n=209
Transfer
n=198
Liveborn
n=97
No Transfer
n=11
Patient Demographics for HIV-seropositive Males
Age (years)
37.2 + 5.6 (22 - 49)
Time from HIV diagnosis (years)
8.3 + 5.6 (1 - 20)
Undetectable viral load
48.9%
Detectable viral load (cps/mL)
3,381.5 + 6,130.9 (53 – 28,424)
CD4 T-cell counts (cells/mm3)
589.0 + 309.4 (13-1,810)
Route of presumed infection
Sexual
37.8%
Transfusions
20.0%
Drug use
5.2%
Unknown
37.0%
Columbia University Results Through 4/2005
Number couples reaching retrieval
135
Number of retrievals
217
Cycle cancellation rate
9.2%
Oocytes per retrieval
16.1 + 9.4 (2-63)
Fertilized oocytes/retrieval
9.1 + 5.2 (0-32)
Embryos per ET
3.2 + 1.1 (1-8)
Clinical pregnancy per retrieval
48.3%
Ongoing/delivered pregnancy rate
43.3%
Ongoing/delivered per couple (includes FETs)
69.0%
Columbia University Results: 4/2005
 Obstetrical outcomes (113 deliveries; 12 ongoing pregnancies)
 Pregnancies from IVF-ICSI
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Singletons
Twins
Triplets
Quadruplets
Multiple gestations
65.5%
32.1%
13.0%
1.1%
46.4%
 Delivery data
 Vaginal births
 Cesarean section
 Term Deliveries
 Gestational age
 Birth weights
 Preterm Deliveries
 Gestational age
 Birth weights
42.2%
57.8%
68.4%
38.9 + 1.1 (37-41 wks)
3501.2 + 491.1 (2550-4396 grams)
31.6%
33.4 + 3.0 (26-36 wks)
2072 + 944.4 (785-2940 grams)
Projecting Efficacy: Female Age Matters
 Life Table Analysis of 164 consecutive fresh treatment cycles
 Best prognosis in women < 34 yrs.
 Majority of pregnancies in 3 cycles
 Delivery rate 2-times better in younger patients
Reprod Biomed Online 2005; 10:130-134.
HCV Co-infected Patients with HIV
 Clinical outcomes for men co-infected with hepatitis C not different from general
population of infertile couples or from couples with HIV infection
28 of 106 HIV seropositive men also co-infected with HCV
54 cycles of ART performed using IVF-ICSI
Delivered pregnancy rate 40% per ET
20 of 28 couples (71%) achieved at least one successful pregnancy
No HIV or HCV seroconversions in patients or offspring
Arch Gynecol Obstet 2005; In press
ASRM Annual Meeting, 2004
Understanding Attitudes and Motivations
 Survey of initial 50 couples regarding demographics, attitudes and motives for
seeking care
 9 couples experienced a previous birth; 3 after knowledge of HIV infection
 12% would attempt pregnancy through intercourse in help unavailable
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48% prefer donor sperm insemination if fertility care unavailable
46% seek continued assistance even if partner died (posthumous therapy)
90% had openly discussed possibility for single parenting
66% hoped to have multiple children through continued ART usage
Obstet Gynecol 2003; 101:987-994.
Columbia University: HIV and Donor Egg
 Experience with oocyte donation
 From 8/97-2/02 53 couples enrolled for IVF-ICSI
 21% deemed ineligible due to advanced reproductive age or lack of ovarian response to
COH
 5 couples elected to pursue oocyte donation with HIV-seropositive partner
 3 of 5 couples delivered following 6 fresh attempts
 2 singleton birth; 1 twin birth
Arch Gynecol Obstet 2003; 268:202-205.
Building Families Through ART
 Greater than 2/3 of couples expressed desire for further attempts after delivery of
a child or children
 5 of 5 couples previously successful were again pregnant following a subsequent
attempt
Fertil Steril 2002; 78:421-423.
Complications Related to ART
 4.6% initiated cycles treated for OHSS
 47% pregnancies multiple gestation
 14% pregnancies higher order multiples
 3 triplet
 1 quadruplet
Arch Gynecol Obstet 2003; 268:198-201.
HIV: Still a Deadly Disease
 LM 38-y/o: died sepsis and liver failure
 PC 42-y/o: died cardiomyopathy and pulmonary hypertension
 MS 47-y/o: died ruptured cerebral aneurysm
 PR 32-y/o: died aseptic meningitis
 MK 31-y/o: died liver failure
ASRM Annual Meeting, 2003.
Importance of Advanced Directives
 Written and witnessed consent for the disposition of fresh and cryopreserved
specimens and embryos
 Clear and convincing evidence of intent of the deceased party in the absence of a
written directive. Such evidence must be personally witnessed by the physician
involved with the procurement of the gametes or embryos.
Ethics Committee Columbia Presbyterian Medical Center 2002
Columbia University Results
 Interesting case reports
 Reversible iatrogenic azospermia secondary to prescribed androgen use
 Posthumous reproduction following the death of a life-partner
Obstet Gynecol 2003; 101:1073-1075.
Am J Obstet Gynecol 2002; 185:252-253.
Initiating a Program for Women with HIV
 Opportunity for HIV seropositive women to access fertility care
 Pre-cycle testing the same as conventional infertility patients
 Additional requirements
 MFM and ID medical clearance
 Maintain minimally detectable titers
 Initiate HAART prior to pregnancy and maintain throughout pregnancy
 Patent tubes: COH and IUI
 Failed IUI or women with tubal obstruction: IVF/ICSI
Initiating a Program for Women with HIV
 Clinical activity began in 2002
 IUI of patients with patent fallopian tubes
 IVF request initially turned down by CPMC ethics committee
 Initial 3 patients treated with COH/IUI
 All 3 women pregnant within 4 treatment cycles
 All newborns HIV seronegative
IVF-ICSI initiated 2004
 3 patients treated; 2 ongoing pregnancies
 7 patients screened and preparing to begin therapy
A Role for Assisted Reproduction?
 Persons with HIV cannot be refused medical treatment unless objective scientific
evidence demonstrates a significant risk of infection.
 Americans with Disabilities Act
 ART should not be denied to HIV-infected couples solely on the basis of their
positive status
 ACOG Committee Opinion 235, 2001
Summation: American Experience
 Although various techniques using washed insemination methods are available,
predominant ART used in U.S. has been IVF-ICSI
 Few centers are currently offering ART to HIV seropositive patients
 Multidisciplinary approach best for providing integrated care by internists,
reproductive endocrinologists, maternal fetal medicine specialists, social workers and
skilled laboratory personnel
 Despite endorsement for treatment by ASRM and ACOG, the CDC continues to
recommend against insemination methods
Conclusion: American Experience
 A slow but growing clinical experience and published literature by U.S. centers has
emerged regarding reproductive care for HIV infected patients
 State laws and concerns related to civil, professional and criminal liability have
hindered wide-spread introduction of methods of treatment
 Studies needed to address the growing needs of HIV infected patients
 Uniformity of approach to care
 Criteria for treatment
 Outcome tracking
 Multicenter collaboration both nationally and internationally