Assisted Reproductive Technology in Resource-Poor Settings

Arlene D. Bardeguez, MD, MPH

Dept. of Obstetrics, Gynecology & Women’s Health

New Jersey Medical School

Definitions

Assisted Reproductive Technologies (ART) include all fertility treatments in which both eggs and sperm are handled.

FCSRCA Publication # 102-493, October 24, 1992.

Reproductive Options for HIV-infected

Women: Historical Perspective USA

1985 Recommendation from CDC: Women known to be HIV(+) should defer pregnancy – concerns disease progression– concerns lethality of disease– concerns of risk perinatal transmission

1990 CDC Reported that Use of Assisted Reproductive Technologies could lead to horizontal transmission

Reproductive Options for HIV-infected Women: Historical Perspective

1994: Use of antiretroviral therapy and/or operative delivery lead to a dramatic decrease in perinatal HIV-1 transmission

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 Transmissionin the HAART Era

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

<1,000 1000-10,000 10-50,000 50-100,000 >100,000

Garcia

Mofenson

Sperling-T

Sperling-P

Perinatal HIV-1 Transmission Rate

@ABardeguez

Mode of Delivery and the Riskof Perinatal HIV-1 Transmission[Meta-Analysis NEJM 1999]

Perinatal transmission Rate among HIV-infected pregnant women

Elective C/Sonly

10.4%

Elective C/S +Antiretroviral [ZDV]

2.0%

NSVD or otheronly

19.0%

NSVD or other +Antiretroviral [ZDV]

7.3%

The Academ y of Medicine of New Jersey

Management of the Management of the HIV+ Pregnant WomanHIV+ Pregnant Woman

Diagnosed Before PregnancyDiagnosed Before PregnancyCase Scenario 2Case Scenario 2

No ARVNo ARV

Diagnosed in PregnancyDiagnosed in PregnancyCase Scenario 1Case Scenario 1

VL >100,000VL >100,000CD4 <350CD4 <350

Diagnosed in LaborDiagnosed in LaborCase Scenario 3Case Scenario 3

Offer Offer shortshort --course course regimen ZDVregimen ZDV

Nevirapine [Nevirapine [ NevNev ]]ZDV+ Nev.ZDV+ Nev.CombivirCombivir

ZDVZDV , 2 NRTI, 2 NRTIHAART [ZDV]HAART [ZDV] HAART (+ZDV)HAART (+ZDV)

On ARVOn ARVVL <1,000VL <1,000

Keep same Keep same regimen unless regimen unless

concern forconcern fortoxicitytoxicity

or or teratogenteratogenVL at term >1,000VL at term >1,000 Infant Infant

RegimenRegimenRefer Mother Refer Mother

and Baby and Baby

Consider C/SConsider C/S

VL <1,000VL <1,000CD4 >350CD4 >350

Guidelines re: HAART

Courtesy of A. Bardeguez, MD

Patient’s Autonomy

Fetal Beneficence

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

Other arguments

Lack of Perinatal transmission can’t be guaranteed

Horizontal transmission risk of available procedures is uncertain [1st do no harm]

Overall cost of Intervention– Individual– Society

Risk/Benefits of Assisted Reproductive Technologies in HIV-Infected Subjects

Could decrease the risk of horizontal transmission for discordant couples– decrease risk of unprotected intercourse– increase conception rate [25% cycle 35% IVF]

Use of reproductive technologies can increase perinatal risk – preterm labor– low birthweight

Could increase morbidity if operative interventions are needed

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

Fecundability 25 %

ICI-IUI1 2-5 %

SO-SO/IUI1 4-9 %

IVF2 35 %

1 Guzick, et al., N Engl J Med 340:177, 1999.2 Fertil Steril 78:918, 2002.

COSTCOST

IVF cycle (1 cycle): $9,226.00

SO-IUI (1 cycle): $1,800.00

SO-IUI (4 cycles): $7,200.00

Semin Reprod Med 331:244, 1994.Fertil Steril 67:830, 1997.

Multiple Gestations per IVF Retrievals-US 1999

0

10

20

30

40

50

60

70

SingletonTwinsTripletsMultiples

Fertil Steril 78:918, 2002.

Assisted Reproductive Technology for Men and Women Infected with Human Immunodeficiency Virus Type 1

Clinical Infectious Diseases

2003; 36: 195-200

January 15, 2003

Case Scenario 1: HIV-Infected Female & Negative Male Partner

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 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!

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 2005

• 39 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”

Semprini et al – Over 1,000 IUI in 350 discordant couples– 200 pregnancies– No horizontal transmission

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]

Sauer et al Complications– Multiple pregnancies– Ovarian stimulation syndrome

Sauer 1997-2002– 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

Risk/Benefits? Optimal Management? Options

– IUI– ICSI– Oocyte Donation– Adoption

Laboratory Issues

Sample processing– Sperm washing– DNA/RNA testing

Prevent Cross-contamination– Timing procedures– Separate freezers for storage– Liquid nitrogen vapors

Criteria and Recommendations for Use of Assisted Reproductive Technologies-I

Disclosure of serostatus between partners Pre-conceptional Counseling Informed consent [risk, benefits, alternatives explained] Absence of OI or prophylaxis CD4>350cells/mm3, HIVRNA <50,000 copies/ml Normal pap and/or colpo if abnormal If Hepatitis C+:

– normal liver enzymes– hepatology consult

Criteria and Recommendations for Use of Assisted Reproductive Technologies-II

Patients receiving HAART: HIV RNA<400 copies/ml Regimen without teratogenic drugs Adequate tolerance to regimen

– No toxicities Adequate response to regimen [CD4, VL] at least

1 year Semen analysis by HIV PCR prior to

insemination/IVF

Criteria and Recommendations for Use of Assisted Reproductive Technologies-III

Intrapartum ZDV prophylaxis Close follow-up during pregnancy and after

birth by HIV experts 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 collectionMonitor outcomes Modify Approaches based on evidenceFinancial Support

Contrast between US orInternational Guidelines, Access to Care

Treatment started if Cd4<350 or viral load >100,000

Unlimited regimens Access to HAART during

pregnancy Access to Intrapartum ZDV C/S done routinely

Treatment started id AIDS or CD4<200

Preferred options for treatment

HAART access limited women with advance disease

NEV used intrapartum Limited access to C/S

Technology Transfer fromDevelop to Under-develop Countries: Cost, Simplicity

Insemination – Sperm Wash Oligo-spermic cap-Sperm Wash IVF ICSI

Ideal Candidate-Individual

Committed couple Younger couple No STI’s Able to use post-exposure prophylaxis Cultural beliefs will not hinder condom use during

pregnancy Able to not breastfeed postpartum Will have access to treatment if disease progress

Ideal Candidate-Community

Access to treatment prior to AIDS diagnosis: diversity of options

Access to IV ZDV in labor or effective antiretroviral for MTCT

Timely and safe access to C/S Access to neonatal antiretrovirals for MTCT

prevention and follow up Long term assessment-cost to society

Ideal Candidate-Site

Assisted reproduction technologies on site Quality control assessment Ongoing training Culturally acceptable Criteria for qualification not link to patient’s

resources

Unknowns!!

Cost effectiveness of averting horizontal and perinatal transmission versus cost intervention

Will current technology for sperm wash be equally effective all clades

Ethics of limiting access to younger population based on fertility rate and life potential

Should access be limited to 1 pregnancy per couple