Assisted Reproductive Technology in Resource-Poor Settings Arlene D. Bardeguez, MD, MPH Dept. of Obstetrics, Gynecology & Women’s Health New Jersey Medical School

Definitions n Assisted Reproductive Technologies (ART) include all fertility treatments in which both eggs and sperm are handled. FCSRCA Publication # , October 24, 1992.

Reproductive Options for HIV-infected Women: Historical Perspective USA n 1985 Recommendation from CDC: Women known to be HIV(+) should defer pregnancy –concerns disease progression –concerns lethality of disease –concerns of risk perinatal transmission n 1990 CDC Reported that Use of Assisted Reproductive Technologies could lead to horizontal transmission

Reproductive Options for HIV-infected Women: Historical Perspective n 1994: Use of antiretroviral therapy and/or operative delivery lead to a dramatic decrease in perinatal HIV-1 transmission n 1996: Introduction of HAART in clinical practice –decrease mortality –increase life-span –increase pool of individuals with stable HIV disease –decrease Perinatal HIV-1 Transmission

Advocates for use of assisted reproductive technologies in HIV- 1 infertile couples

Perinatal HIV-1 Transmission in the HAART Era Perinatal HIV-1 Transmission

Mode of Delivery and the Risk of Perinatal HIV-1 Transmission [Meta-Analysis NEJM 1999] Perinatal transmission Rate among HIV-infected pregnant women Elective C/S only 10.4% Elective C/S + Antiretroviral [ZDV] 2.0% NSVD or other only 19.0% NSVD or other + Antiretroviral [ZDV] 7.3%

Patient’s Autonomy Fetal Beneficence

Opponents on the use of assisted reproductive technologies in HIV-1 infertile couples

Other arguments n Lack of Perinatal transmission can’t be guaranteed n Horizontal transmission risk of available procedures is uncertain [1 st do no harm] n Overall cost of Intervention –Individual –Society

Risk/Benefits of Assisted Reproductive Technologies in HIV-Infected Subjects n Could decrease the risk of horizontal transmission for discordant couples –decrease risk of unprotected intercourse –increase conception rate [25% cycle 35% IVF] n Use of reproductive technologies can increase perinatal risk –preterm labor –low birthweight n Could increase morbidity if operative interventions are needed n Increase cost of the interventions?

Assisted Reproductive Technologies should not be denied to HIV-infected couples solely on the basis of their positive serostatus Committee on Ethics of ACOG 2001 American Society for Reproductive Medicine 2002

Something to Think About! By 1999, more than 97% of all ART procedures in the United States were IVF + ICSI. Fertil Steril 78:918, 2002.

Pregnancy Rates According to Procedure Used Pregnancy/Cycle Fecundability25 % ICI-IUI % SO-SO/IUI % IVF 2 35 % 1 Guzick, et al., N Engl J Med 340:177, Fertil Steril 78:918, 2002.

COST n IVF cycle (1 cycle): $9, n SO-IUI (1 cycle):$1, n SO-IUI (4 cycles):$7, Semin Reprod Med 331:244, Fertil Steril 67:830, 1997.

Multiple Gestations per IVF Retrievals-US 1999 Fertil Steril 78:918, 2002.

Assisted Reproductive Technology for Men and Women Infected with Human Immunodeficiency Virus Type 1 Clinical Infectious Diseases 2003; 36: January 15, 2003

Case Scenario 1: HIV-Infected Female & Negative Male Partner n Goals –Prevent horizontal transmission Artificial insemination with/without ovarian stimulation Donor Insemination IVF –Prevent perinatal transmission –Infertility work-up if needed Anovulation [PCO, Substance use, Hypothalamic disorders, HIV?]

Case Scenario 2: HIV-Infected Male & Negative Female Partner Goals n Prevent horizontal transmission –Cell associated and cell free virus can be source of infection –There is a relation between serum and genital viral load but imperfect! n Techniques used –Intrauterine insemination after “Sperm wash” –Intracytoplasmic Sperm Injection [ICSI] –Oocyte donation

Bedford Research Foundation* Special Program of Assisted Reproduction-SPAR Pregnancies and Births as of January pregnancies have been achieved through SPAR and IVF, procedures, 6 are ongoing. 3 pregnancies and 3 births have been achieved using the new Oligospermic Cup procedure, both are ongoing. 26 babies have been born using SPAR and IVF procedures 5 sets of twins 16 singletons *Formerly Duncan Holly Biomedical Inc.

Intrauterine insemination after “Sperm wash” n Semprini et al –Over 1,000 IUI in 350 discordant couples –200 pregnancies –No horizontal transmission n Marina et al –63 HIV+ men without AIDS –+ HIV RNA 5.6% samples [discarded] –49% success IUI, 37 children –All women HIV(-) 6 months after IUI

Intracytoplasmic Sperm Injection [ICSI] n Sauer et al Complications –Multiple pregnancies –Ovarian stimulation syndrome n Sauer –25 couples conceived 27 pregnancies –40 neonates –C/S rate 70% –Mean gestational age at delivery 37 weeks –7 cases Preterm delivery –8 cases low birth weight

Case Scenario 3: Both partners HIV-Infected n Risk/Benefits? n Optimal Management? n Options –IUI –ICSI –Oocyte Donation –Adoption

Laboratory Issues n Sample processing –Sperm washing –DNA/RNA testing n Prevent Cross-contamination –Timing procedures –Separate freezers for storage –Liquid nitrogen vapors

Criteria and Recommendations for Use of Assisted Reproductive Technologies-I n Disclosure of serostatus between partners n Pre-conceptional Counseling n Informed consent [risk, benefits, alternatives explained] n Absence of OI or prophylaxis n CD4>350cells/mm 3, HIVRNA <50,000 copies/ml n Normal pap and/or colpo if abnormal n If Hepatitis C+: –normal liver enzymes – hepatology consult

Criteria and Recommendations for Use of Assisted Reproductive Technologies-II Patients receiving HAART: n HIV RNA<400 copies/ml n Regimen without teratogenic drugs n Adequate tolerance to regimen –No toxicities n Adequate response to regimen [CD4, VL] at least 1 year n Semen analysis by HIV PCR prior to insemination/IVF

Criteria and Recommendations for Use of Assisted Reproductive Technologies-III n Intrapartum ZDV prophylaxis n Close follow-up during pregnancy and after birth by HIV experts n Follow-up of child and HIV negative partner after procedure/delivery to verify lack of transmission

Patients Technology Outcomes Optimal candidates Access Attitudes/Beliefs Education Optimal procedures Sperm washing Drug penetration Ethics:Risk/Benefits Access Data collection Monitor outcomes Modify Approaches based on evidence Financial Support

Contrast between US or International Guidelines, Access to Care n Treatment started if Cd4 100,000 n Unlimited regimens n Access to HAART during pregnancy n Access to Intrapartum ZDV n C/S done routinely n Treatment started id AIDS or CD4<200 n Preferred options for treatment n HAART access limited women with advance disease n NEV used intrapartum n Limited access to C/S

Technology Transfer from Develop to Under-develop Countries: Cost, Simplicity n Insemination – Sperm Wash n Oligo-spermic cap-Sperm Wash n IVF n ICSI

Ideal Candidate-Individual n Committed couple n Younger couple n No STI’s n Able to use post-exposure prophylaxis n Cultural beliefs will not hinder condom use during pregnancy n Able to not breastfeed postpartum n Will have access to treatment if disease progress

Ideal Candidate-Community n Access to treatment prior to AIDS diagnosis: diversity of options n Access to IV ZDV in labor or effective antiretroviral for MTCT n Timely and safe access to C/S n Access to neonatal antiretrovirals for MTCT prevention and follow up n Long term assessment-cost to society

Ideal Candidate-Site n Assisted reproduction technologies on site n Quality control assessment n Ongoing training n Culturally acceptable n Criteria for qualification not link to patient’s resources

Unknowns!! n Cost effectiveness of averting horizontal and perinatal transmission versus cost intervention n Will current technology for sperm wash be equally effective all clades n Ethics of limiting access to younger population based on fertility rate and life potential n Should access be limited to 1 pregnancy per couple