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Treatment of Infertility in HIV Discordant Couples
M.V. Sauer
College of Physicians & Surgeons, Columbia University, New York, New York U.S.A.
Summary
Increasingly, HIV-1 seropositive individuals are living active and productive lives as a
result of highly active antiretroviral therapy (HAART). Most infected patients are of
reproductive age, and would normally desire to begin families. During the past ten years
assisted reproductive techniques (ART) have been introduced to reduce or eliminate the
infectious material known to exist in semen. Several European clinics and a few U.S.
centers offer assistance to HIV-serodiscordant couples in order to prevent infection in the
seronegative partner. Treatments involve seropositive men and seronegative women
undergoing either intrauterine insemination or in vitro fertilization (IVF). Since 1987
more than 3,000 treatment cycles have been reported using processed sperm from HIV-1
seropositive men without a documented seroconversion.
Introduction
Controversy surrounds the issue of whether ART should be offered to couples in whom
the male partner is known to be HIV-1 seropositive.(1,2) HIV-1 infection occurs
primarily in young, reproductively healthy males, many of whom would normally desire
to father a child.(3) However, safe sexual practices, including the use of condoms,
precludes any hope of the pregnancy outside of donor sperm insemination. Reproductive
drive is incredibly strong, and patients are known to take risks in order to have a baby
beyond what may be reasonable. Seroconversion has occurred as a result of timed
intercourse. Interviews conducted as part of the HIV Cost and Services Utilization Study
of 2,864 HIV-infected adults in the United States discovered that 28-29% desire children
in the future.(4)
The use of sperm preparation techniques, known as “sperm washing”, to reduce the
chance of horizontal transmission has been recommended for nearly 10 years.(5) Yet,
there are few practitioners willing to offer assisted reproductive therapy for fear of
infecting the seronegative partner and child. Furthermore, several professional societies,
including the Centers for Disease Control(CDC) have published recommendations
against treating serodiscordant couples.(6,7) These prohibitions were largely based upon
information available prior to 1990, a time in which infection with HIV-1 was typically
considered a terminal illness. Recently, the American College of Obstetricians and
Gynecologists(ACOG) and the American Society for Reproductive Medicine(ASRM)
have revised their earlier statements against treating discordant couples, and
recommended policies of nondiscrimination.(8,9)
Preliminary reports from centers that performed washed sperm preparation and
intrauterine insemination (IUI) demonstrated safety, with no seroconversions occurring in
women or their offspring. However, concerns with respect to introducing infection
persisted since IUI therapy requires millions of sperm cells to be placed above the natural
immunological barrier of the cervix. It is difficult to ensure that all CD4 receptor cells are
washed free in the preparation. HIV-1 RNA has been detected in purified seminal
macrophages and lymphocytes but not typically not in germ cells or viable
spermatozoa.(10) With these concerns in mind, Columbia University elected to offer a
therapy which lowers viral exposure to the level of a few motile sperm cells.
Intracytoplasmic sperm injection (ICSI) is commonly used to address male factor
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infertility.(11) Sperm washing techniques are used prior to ICSI and the resultant motile
sperm found in the supernatant following swim-up are used. HIV-1 has been most
frequently cultured from the cellular fraction of semen, and in general HIV-1 RNA levels
in semen only weakly correlate with HIV-1 RNA levels in blood plasma.(12) Thus, IVFICSI was chosen as a preventive measure to reduce the risk of horizontal transmission of
HIV-1.
Material and Methods
The published results from clinical studies were reviewed.(13-25) Only studies which
included the follow-up surveillance of participants were analyzed. In 1997 the Ethics
Committee of Columbia Presbyterian Medical Center considered a request to allow HIV1 serodiscordant couples access to assisted reproductive care. A protocol was approved
by the Institutional Review Board of the medical center to study the efficacy of treating
serodiscordant couples using IVF-ICSI.
Enrollment Criteria
Men were under medical surveillance for their infection and if indicated, taking antiviral
medications. Plasma HIV RNA counts and CD 4 status were ascertained. Men were
infected through a variety of ways including transfusion therapy, sex and intravenous
drug use. Female partners were HIV-1 tested (HIV enzyme immunoassay; HIV-EIA) and
required to be seronegative. Couples had to be using condoms and practicing safe sex.
Women underwent a gyn examination and serum estradiol (E2) and follicle stimulating
hormone levels (FSH) were drawn to ascertain the appropriateness of IVF therapy.
IVF-ICSI Cycle and Follow-up
Standard pre-cycle procedures used in ART were provided. Needle aspiration of the
oocytes was timed 34-36 hours following hCG injection. A fresh semen sample was used
for ICSI and processed by centrifuging it through a discontinuous density as previously
described.(25) Ultrasound guided transcervical transfers at 72 hours were used in all
cases. Patients were tested for pregnancy 12 days following transfer. Serial blood testing
(HIV-EIA) was repeated throughout pregnancy during each trimester. At delivery and 3
months postpartum mothers were tested using HIV-DNA PCR. Newborns were also
tested at birth and 3 months of age with HIV-DNA PCR. Patients failing to become
pregnant or women who experienced spontaneous abortion were asked to repeat their
HIV-EIA tests 3 and 6 months later.
Results
Table 1 summarizes the results of treatment of HIV-1 serodiscordant couples using both
IUI and IVF methodology. In our experience(25) with IVF-ICSI there were no
seroconversions in women (n=34) or offspring (n=25) following 55 ETs. Treatment
efficacy was similar to normal controls undergoing IVF-ICSI for the treatment of male
factor infertility; retrieved eggs (15.8 + 1.3 vs. 12.3 + 0.8); fertilization rate (64.9% vs.
68.0%); embryos cryopreserved (1.1 + 0.3 vs. 0.3 + 0.1, p<0.05); clinical pregnancies/ET
(45.5% vs. 35.4%); ongoing/delivered pregnancies/ET (30.9% vs. 25.0%). Spontaneous
abortions occurred in 20.6% of pregnant women, not significantly different from controls.
Multiple gestations were noted in 6 of 17 delivered pregnancies (35.3%). Two of the 17
pregnancies (11.8%) were triplets. All 6 preterm deliveries occurred in patients with
multiple gestations. There were no complications reported in the newborns secondary to
prematurity. Most pregnancies occurred within the first three attempts at IVF-ICSI. Half
(17/34) of all couples making it to retrieval successfully achieved a viable pregnancy.
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There were no seroconversions in any of the 34 patients receiving one or more of the 55
embryo transfers. All 25 delivered infants were HIV negative at birth and at 3 months of
age.
Conclusions
Cognizant of the concerns regarding disease transmission, the purpose of all clinical trials
involving sperm separation is to provide HIV-1 serodiscordant couples an opportunity to
have a child without risk. Various techniques have been suggested as a preventive
measure for avoiding infection in HIV-1 serodiscordant couples intent on reproducing.
ICSI requires only the in-vitro contact of a single sperm and egg, and should dramatically
reduce the risk of transferring viral particles that are often present in the semen. IVF-ICSI
should prevent infection and allow serodiscordant couples success rates similar to other
patients routinely treated with IVF-ICSI for male factor infertility.(25)
The commonly accepted principles of health care ethics include consideration of respect
for autonomy, non-maleficence, beneficence and justice.(26) Each of these tenets were
individually considered in making the decision to treat. Informed and rationale decision
making must occur in every case of intervention. A lengthy discussion of the natural
history of HIV infection, and the biology of transmission should precede treatment.
Reproductive alternatives, including artificial insemination with donor sperm, adoption,
and childless living should be offered. Patients must act intentionally and without
controlling influences that would mitigate against a free and voluntary act. Most
importantly, women need to understand that none of the procedures are risk free, and all
carry a small possibility for infection.
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Table1. Summary of HIV-1 Serodiscordant Couples Undergoing ART