- Email: [email protected]
Successive pregnancies with delivery of two healthy infants in a couple who was discordant for human immunodeficiency virus infection
FERTILITY AND STERILITY威 VOL. 78, NO. 2, AUGUST 2002 Copyright ©2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Successive pregnancies with delivery of two healthy infants in a couple who was discordant for human immunodeficiency virus infection Joseph E. Pen˜a, M.D., Jeff Klein, M.D., Melvin Thornton II, M.D., Peter L. Chang, M.D., and Mark V. Sauer, M.D. College of Physicians and Surgeons, Columbia University, New York, New York
Objective: To describe two successive pregnancies resulting in two healthy infants in an HIV-discordant couple who underwent IVF-ICSI. Design: Case report. Setting: University-based infertility clinic. Patient(s): A couple seeking fertility treatment in which the male partner was seropositive for HIV-1. Intervention(s): Controlled ovarian hyperstimulation and IVF-ET with ICSI. Main Outcome Measure(s): Pregnancy outcome and HIV-1 seroconversion. Result(s): The couple delivered two healthy infants on successive pregnancies with use of IVF-ET with ICSI. Conclusion(s): For HIV-discordant couples in which the male partner is seropositive for HIV-1, IVF with ICSI is a viable option. (Fertil Steril威 2002;78:421–3. ©2002 by American Society for Reproductive Medicine.) Key Words: HIV, ICSI, IVF, pregnancy, reproduction
Received October 10, 2001; revised and accepted January 25, 2002. Reprint requests: Mark V. Sauer, M.D., Department of Obstetrics and Gynecology, ColumbiaPresbyterian Medical Center 622 West 168th Street, PH 16-28, New York, New York 10032 (FAX: 212-342-2206; Email: [email protected]). 0015-0282/02/$22.00 PII S0015-0282(02)03213-2
More than 30 million persons worldwide are infected with HIV. In HIV-discordant couples in which the man is seropositive for HIV-1 but the woman is seronegative, sexual intercourse in the absence of safer-sex precautions carries a significant risk for HIV-1 transmission; annual rates of disease transmission are as high as 7.2% (1). For couples who desire a child, this risk severely limits their reproductive options.
sperm from HIV-positive men has emerged as a potentially safe alternative; hundreds of pregnancies have been reported to date without a documented conversion (2– 4). Others have investigated use of IVF-ICSI to reduce the exposure to sperm to a few gametes (5, 6). Our experience supports that IVF-ET with ICSI in HIV-1– discordant couples in which the male partner is seropositive is a viable option.
Artificial insemination with semen from an HIV-negative donor remains the safest, most accepted alternative. However, patients are often reluctant to accept a sperm donor, particularly if they have an otherwise normal reproductive ability.
Because the duration of disease-free survival of HIV-1–seropositive persons is increasing, many couples who have achieved a successful pregnancy may opt to have further children. We report on the first live births of two uninfected children from consecutive pregnancies in an HIV-1–serodiscordant couple who conceived through IVF-ICSI and ET.
The safety of assisted reproduction using sperm from HIV-1–seropositive persons is an ongoing topic of research. Yet, appropriately counseled couples who wish to safely conceive now have an alternative to natural conception and its attendant transmission risk. In the past decade, intrauterine insemination with washed
CASE REPORT Use of IVF-ICSI in HIV-1–serodiscordant couples was reviewed and approved by the 421
institutional review board and ethics committee of Columbia-Presbyterian Medical Center. An African-American HIV-serodiscordant couple presented to our center for reproductive counseling. The man, 47 years of age, was known to be HIV-1 seropositive for 8 years. He had been married to his wife during this time and had always used a condom since his diagnosis to avoid transmission of the virus. He denied a history of intravenous drug use, and the HIV infection was presumably acquired through sexual contact. His first wife died of AIDS. Infectious disease screening tests were negative for chlamydia, gonorrhea, syphilis, and hepatitis. His medical history was unremarkable except for mild hypertension and hypercholesterolemia controlled by diet. He had no history of opportunistic infections. He had been followed by an infectious disease specialist since diagnosis of HIV and had not received antiretroviral therapy. His CD4⫹ lymphocyte count and HIV viral load before enrollment in our IVF program were 606 cells/L and 6657 copies/mL, respectively. Semen analysis was normal. The woman, 33 years of age, was HIV-1 seronegative and had no previous pregnancies. She denied a history of sexually transmitted diseases. Infectious disease screening was negative for chlamydia, gonorrhea, syphilis, hepatitis, and HIV. The couple was counseled extensively that IVF-ICSI is not the standard of care and there is no guarantee the woman or infant would not be at risk for infection. The couple accepted this and elected to proceed with treatment. The woman underwent standard down-regulation using leuprolide acetate followed by ovarian hyperstimulation with gonadotropin (hMG). Ovarian response was assessed by ultrasonography and serum estradiol levels, and hCG was administered when lead follicles reached 19 –20 mm in diameter. Ultrasonography-guided transvaginal oocyte retrieval was performed 34 –36 hours later under intravenous conscious sedation. All visible follicles were aspirated, and 13 oocytes were collected. Twelve mature oocytes were suitable for ICSI. Sperm were prepared by using a doublewash swim-up method modified from that described elsewhere (2). Eight oocytes fertilized normally (two pronuclei), and on day 3, four embryos were transferred into the uterine cavity.
-Human chorionic gonadotropin testing was positive 2 weeks after ET, and a single intrauterine pregnancy was confirmed 1 week later by transvaginal ultrasonography. The patient was tested with HIV enzyme immunoassay each trimester and remained seronegative. She delivered a healthy male infant weighing 9 pounds 8 ounces (4309 g) at term by cesarean section owing to arrest of the active phase of labor. The woman tested negative for HIV-1 antibodies immediately postpartum and 6 months afterward. The infant tested negative for HIV DNA on polymerase chain reaction at delivery and at 3 and 6 months postpartum. 422
Pen˜a et al.
IVF in an HIV-discordant couple
A year and a half after the birth of their son, the couple returned to our department because they desired another child. The husband remained healthy, and the couple had used condoms during this interval. They were once again counseled and screened. In the interim, the husband had elected to begin treatment with indinavir. Before initiation of the IVF-ICSI cycle, the husband’s CD4⫹ lymphocyte count was 621 cells/L and his viral load was ⬍50 copies/mL. The woman remained HIV-1 seronegative. Ovarian stimulation was achieved by using the same regimen as before. After ovarian stimulation treatment, nine oocytes were aspirated and used for ICSI. Six oocytes fertilized normally, and on day 3, four embryos were transferred. After ET, a -hCG test was positive, and a single intrauterine pregnancy was confirmed. The woman delivered her second baby at term by elective cesarean section. The mother tested negative for HIV-1 antibodies throughout pregnancy and postpartum. The infant tested negative for HIV-DNA at birth and 3 and 6 months postpartum.
DISCUSSION HIV has significantly affected human reproduction in terms of its widespread prevalence and its effect on the ability to safely conceive a child if one partner is infected. Because of advances in antiretroviral therapy and improvement in the treatment of opportunistic infections, the average disease-free interval of HIV-infected persons has increased to more than 10 years from the time of viral transmission to an AIDS-defining diagnosis (7) and to almost 4 years after an AIDS-defining diagnosis (8). The improvement in the quality of life and the increase in the asymptomatic period of infected persons have given many the hope of starting a family and living a “normal life.” When contemplating pregnancy, uninfected female partners are counseled that the safest option is to inseminate with semen from an HIV-negative donor. However, many couples strongly desire to have their own biological children. Practitioners of fertility care in the United States have been discouraged from offering reproductive care to HIV-discordant couples (9, 10). This has led to a general reluctance to accept discordant patients for treatment. As a result, many Americans have gone to Europe for treatment, where such care is not discouraged. Human immunodeficiency virus is believed to exist in seminal plasma, nongamete cells (lymphocytes and macrophages), and nonmotile spermatozoa (11, 12). However, some evidence indicates that HIV particles may also be found in motile spermatozoa (13–15). Thus, any insemination poses some risk for transmission. Washed insemination requires millions of sperm to be deposited above the immunologic barrier of the cervix. In contrast, ICSI reduces the inoculum of HIV particles (if they Vol. 78, No. 2, August 2002
are present in motile sperm) by a factor of 106, since an oocyte is exposed to only a single spermatozoon. Preliminary data have shown that IVF-ICSI using processed semen is safe in HIV-1– discordant couples in which the man is seropositive (4 – 6). Couples who are HIV-1 serodiscordant often desire to have biological children of their own and hope to minimize the risk for transmission of HIV-1 to the mother and child. In these couples, IVF-ICSI is a suitable preventive measure. A decade ago, HIV-1–serodiscordant couples were not routinely considered candidates for reproductive care. Advances in ART (such as sperm washing techniques and IVF-ICSI), coupled with the improvements in HIV care, now permit couples to raise a family and remain healthy. References 1. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G, et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr 1993;6:497–502. 2. Semprini AE, Levi-Setti P, Bozzo M, Ravizza M, Taglioretti A, Sulpizio P, et al. Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet 1992;340:1317–9. 3. Semprini AE, Fiore S, Pardi G. Reproductive counselling for HIVdiscordant couples. Lancet 1997;349:1401–2. 4. Marina S, Marina F, Alcolea R, Exposito R, Huguet J, Nadal J, et al. Human immunodeficiency virus type 1–serodiscordant couples can
FERTILITY & STERILITY威
5. 6.
7. 8. 9. 10. 11. 12.
13. 14. 15.
bear healthy children after undergoing intrauterine insemination. Fertil Steril 1998;70:35–9. Marina S, Marina F, Alcolea R, Nadal J, Exposito R, Huguet J. Pregnancy following intracytoplasmic sperm injection from an HIV-1seropositive man. Hum Reprod 1998;13:3247–9. Loutradis D, Drakakis P, Kallianidis K, Patsoula E, Bletsa R, Michalas S. Birth of two infants who were seronegative for human immunodeficiency virus type 1 (HIV-1) after intracytoplasmic injection of sperm from HIV-1-seropositive men. Fertil Steril 2001;75:210 –2. Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124:654 – 63. Lee LM, Karon JM, Selik R, Neal JJ, Fleming PL. Survival after AIDS diagnosis in adolescents and adults during the treatment era, United States, 1984-1997. JAMA 2001;285:1308 –15. HIV-1 infection and artificial insemination with processed semen. MMWR Morb Mortal Wkly Rep 1990;39:249, 255– 6. American Society for Reproductive Medicine. Fertil Steril 1993;59:1– 39. Mermin JH, Holodniy M, Katzenstein DA, Merigan TC. Detection of human immunodeficiency virus DNA and RNA in semen by the polymerase chain reaction. J Infect Dis 1991;164:769 –72. Van Voorhis BJ, Martinez A, Mayer K, Anderson DJ. Detection of human immunodeficiency virus type 1 in semen from seropositive men using culture and polymerase chain reaction deoxyribonucleic acid amplification techniques. Fertil Steril 1991;55:588 –94. Bagasra O, Farzadegan H, Seshamma T, Oakes JW, Saah A, Pomerantz RJ. Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. AIDS 1994;8:1669 –74. Scofield VL, Rao B, Broder S, Kennedy C, Wallace M, Graham B, et al. HIV interaction with sperm. AIDS 1994;8:1733– 6. Baccetti B, Benedetto A, Collodel G, di Caro A, Garbuglia AR, Piomboni P. The debate on the presence of HIV-1 in human gametes. J Reprod Immunol 1998;41:41– 67.
423
Successive pregnancies with delivery of two healthy infants in a couple who was discordant for human immunodeficiency virus infection Joseph E. Pen˜a, M.D., Jeff Klein, M.D., Melvin Thornton II, M.D., Peter L. Chang, M.D., and Mark V. Sauer, M.D. College of Physicians and Surgeons, Columbia University, New York, New York
Objective: To describe two successive pregnancies resulting in two healthy infants in an HIV-discordant couple who underwent IVF-ICSI. Design: Case report. Setting: University-based infertility clinic. Patient(s): A couple seeking fertility treatment in which the male partner was seropositive for HIV-1. Intervention(s): Controlled ovarian hyperstimulation and IVF-ET with ICSI. Main Outcome Measure(s): Pregnancy outcome and HIV-1 seroconversion. Result(s): The couple delivered two healthy infants on successive pregnancies with use of IVF-ET with ICSI. Conclusion(s): For HIV-discordant couples in which the male partner is seropositive for HIV-1, IVF with ICSI is a viable option. (Fertil Steril威 2002;78:421–3. ©2002 by American Society for Reproductive Medicine.) Key Words: HIV, ICSI, IVF, pregnancy, reproduction
Received October 10, 2001; revised and accepted January 25, 2002. Reprint requests: Mark V. Sauer, M.D., Department of Obstetrics and Gynecology, ColumbiaPresbyterian Medical Center 622 West 168th Street, PH 16-28, New York, New York 10032 (FAX: 212-342-2206; Email: [email protected]). 0015-0282/02/$22.00 PII S0015-0282(02)03213-2
More than 30 million persons worldwide are infected with HIV. In HIV-discordant couples in which the man is seropositive for HIV-1 but the woman is seronegative, sexual intercourse in the absence of safer-sex precautions carries a significant risk for HIV-1 transmission; annual rates of disease transmission are as high as 7.2% (1). For couples who desire a child, this risk severely limits their reproductive options.
sperm from HIV-positive men has emerged as a potentially safe alternative; hundreds of pregnancies have been reported to date without a documented conversion (2– 4). Others have investigated use of IVF-ICSI to reduce the exposure to sperm to a few gametes (5, 6). Our experience supports that IVF-ET with ICSI in HIV-1– discordant couples in which the male partner is seropositive is a viable option.
Artificial insemination with semen from an HIV-negative donor remains the safest, most accepted alternative. However, patients are often reluctant to accept a sperm donor, particularly if they have an otherwise normal reproductive ability.
Because the duration of disease-free survival of HIV-1–seropositive persons is increasing, many couples who have achieved a successful pregnancy may opt to have further children. We report on the first live births of two uninfected children from consecutive pregnancies in an HIV-1–serodiscordant couple who conceived through IVF-ICSI and ET.
The safety of assisted reproduction using sperm from HIV-1–seropositive persons is an ongoing topic of research. Yet, appropriately counseled couples who wish to safely conceive now have an alternative to natural conception and its attendant transmission risk. In the past decade, intrauterine insemination with washed
CASE REPORT Use of IVF-ICSI in HIV-1–serodiscordant couples was reviewed and approved by the 421
institutional review board and ethics committee of Columbia-Presbyterian Medical Center. An African-American HIV-serodiscordant couple presented to our center for reproductive counseling. The man, 47 years of age, was known to be HIV-1 seropositive for 8 years. He had been married to his wife during this time and had always used a condom since his diagnosis to avoid transmission of the virus. He denied a history of intravenous drug use, and the HIV infection was presumably acquired through sexual contact. His first wife died of AIDS. Infectious disease screening tests were negative for chlamydia, gonorrhea, syphilis, and hepatitis. His medical history was unremarkable except for mild hypertension and hypercholesterolemia controlled by diet. He had no history of opportunistic infections. He had been followed by an infectious disease specialist since diagnosis of HIV and had not received antiretroviral therapy. His CD4⫹ lymphocyte count and HIV viral load before enrollment in our IVF program were 606 cells/L and 6657 copies/mL, respectively. Semen analysis was normal. The woman, 33 years of age, was HIV-1 seronegative and had no previous pregnancies. She denied a history of sexually transmitted diseases. Infectious disease screening was negative for chlamydia, gonorrhea, syphilis, hepatitis, and HIV. The couple was counseled extensively that IVF-ICSI is not the standard of care and there is no guarantee the woman or infant would not be at risk for infection. The couple accepted this and elected to proceed with treatment. The woman underwent standard down-regulation using leuprolide acetate followed by ovarian hyperstimulation with gonadotropin (hMG). Ovarian response was assessed by ultrasonography and serum estradiol levels, and hCG was administered when lead follicles reached 19 –20 mm in diameter. Ultrasonography-guided transvaginal oocyte retrieval was performed 34 –36 hours later under intravenous conscious sedation. All visible follicles were aspirated, and 13 oocytes were collected. Twelve mature oocytes were suitable for ICSI. Sperm were prepared by using a doublewash swim-up method modified from that described elsewhere (2). Eight oocytes fertilized normally (two pronuclei), and on day 3, four embryos were transferred into the uterine cavity.
-Human chorionic gonadotropin testing was positive 2 weeks after ET, and a single intrauterine pregnancy was confirmed 1 week later by transvaginal ultrasonography. The patient was tested with HIV enzyme immunoassay each trimester and remained seronegative. She delivered a healthy male infant weighing 9 pounds 8 ounces (4309 g) at term by cesarean section owing to arrest of the active phase of labor. The woman tested negative for HIV-1 antibodies immediately postpartum and 6 months afterward. The infant tested negative for HIV DNA on polymerase chain reaction at delivery and at 3 and 6 months postpartum. 422
Pen˜a et al.
IVF in an HIV-discordant couple
A year and a half after the birth of their son, the couple returned to our department because they desired another child. The husband remained healthy, and the couple had used condoms during this interval. They were once again counseled and screened. In the interim, the husband had elected to begin treatment with indinavir. Before initiation of the IVF-ICSI cycle, the husband’s CD4⫹ lymphocyte count was 621 cells/L and his viral load was ⬍50 copies/mL. The woman remained HIV-1 seronegative. Ovarian stimulation was achieved by using the same regimen as before. After ovarian stimulation treatment, nine oocytes were aspirated and used for ICSI. Six oocytes fertilized normally, and on day 3, four embryos were transferred. After ET, a -hCG test was positive, and a single intrauterine pregnancy was confirmed. The woman delivered her second baby at term by elective cesarean section. The mother tested negative for HIV-1 antibodies throughout pregnancy and postpartum. The infant tested negative for HIV-DNA at birth and 3 and 6 months postpartum.
DISCUSSION HIV has significantly affected human reproduction in terms of its widespread prevalence and its effect on the ability to safely conceive a child if one partner is infected. Because of advances in antiretroviral therapy and improvement in the treatment of opportunistic infections, the average disease-free interval of HIV-infected persons has increased to more than 10 years from the time of viral transmission to an AIDS-defining diagnosis (7) and to almost 4 years after an AIDS-defining diagnosis (8). The improvement in the quality of life and the increase in the asymptomatic period of infected persons have given many the hope of starting a family and living a “normal life.” When contemplating pregnancy, uninfected female partners are counseled that the safest option is to inseminate with semen from an HIV-negative donor. However, many couples strongly desire to have their own biological children. Practitioners of fertility care in the United States have been discouraged from offering reproductive care to HIV-discordant couples (9, 10). This has led to a general reluctance to accept discordant patients for treatment. As a result, many Americans have gone to Europe for treatment, where such care is not discouraged. Human immunodeficiency virus is believed to exist in seminal plasma, nongamete cells (lymphocytes and macrophages), and nonmotile spermatozoa (11, 12). However, some evidence indicates that HIV particles may also be found in motile spermatozoa (13–15). Thus, any insemination poses some risk for transmission. Washed insemination requires millions of sperm to be deposited above the immunologic barrier of the cervix. In contrast, ICSI reduces the inoculum of HIV particles (if they Vol. 78, No. 2, August 2002
are present in motile sperm) by a factor of 106, since an oocyte is exposed to only a single spermatozoon. Preliminary data have shown that IVF-ICSI using processed semen is safe in HIV-1– discordant couples in which the man is seropositive (4 – 6). Couples who are HIV-1 serodiscordant often desire to have biological children of their own and hope to minimize the risk for transmission of HIV-1 to the mother and child. In these couples, IVF-ICSI is a suitable preventive measure. A decade ago, HIV-1–serodiscordant couples were not routinely considered candidates for reproductive care. Advances in ART (such as sperm washing techniques and IVF-ICSI), coupled with the improvements in HIV care, now permit couples to raise a family and remain healthy. References 1. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G, et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr 1993;6:497–502. 2. Semprini AE, Levi-Setti P, Bozzo M, Ravizza M, Taglioretti A, Sulpizio P, et al. Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet 1992;340:1317–9. 3. Semprini AE, Fiore S, Pardi G. Reproductive counselling for HIVdiscordant couples. Lancet 1997;349:1401–2. 4. Marina S, Marina F, Alcolea R, Exposito R, Huguet J, Nadal J, et al. Human immunodeficiency virus type 1–serodiscordant couples can
FERTILITY & STERILITY威
5. 6.
7. 8. 9. 10. 11. 12.
13. 14. 15.
bear healthy children after undergoing intrauterine insemination. Fertil Steril 1998;70:35–9. Marina S, Marina F, Alcolea R, Nadal J, Exposito R, Huguet J. Pregnancy following intracytoplasmic sperm injection from an HIV-1seropositive man. Hum Reprod 1998;13:3247–9. Loutradis D, Drakakis P, Kallianidis K, Patsoula E, Bletsa R, Michalas S. Birth of two infants who were seronegative for human immunodeficiency virus type 1 (HIV-1) after intracytoplasmic injection of sperm from HIV-1-seropositive men. Fertil Steril 2001;75:210 –2. Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124:654 – 63. Lee LM, Karon JM, Selik R, Neal JJ, Fleming PL. Survival after AIDS diagnosis in adolescents and adults during the treatment era, United States, 1984-1997. JAMA 2001;285:1308 –15. HIV-1 infection and artificial insemination with processed semen. MMWR Morb Mortal Wkly Rep 1990;39:249, 255– 6. American Society for Reproductive Medicine. Fertil Steril 1993;59:1– 39. Mermin JH, Holodniy M, Katzenstein DA, Merigan TC. Detection of human immunodeficiency virus DNA and RNA in semen by the polymerase chain reaction. J Infect Dis 1991;164:769 –72. Van Voorhis BJ, Martinez A, Mayer K, Anderson DJ. Detection of human immunodeficiency virus type 1 in semen from seropositive men using culture and polymerase chain reaction deoxyribonucleic acid amplification techniques. Fertil Steril 1991;55:588 –94. Bagasra O, Farzadegan H, Seshamma T, Oakes JW, Saah A, Pomerantz RJ. Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. AIDS 1994;8:1669 –74. Scofield VL, Rao B, Broder S, Kennedy C, Wallace M, Graham B, et al. HIV interaction with sperm. AIDS 1994;8:1733– 6. Baccetti B, Benedetto A, Collodel G, di Caro A, Garbuglia AR, Piomboni P. The debate on the presence of HIV-1 in human gametes. J Reprod Immunol 1998;41:41– 67.
423