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The objective of the study was to evaluate the safety of semen washing with intrauterine insemination (SW-IUI) for achieving pregnancy when the man is human immunodeficiency virus (HIV) infected and the woman is HIV negative.
Study Design
We conducted a retrospective analysis of 635 HIV-discordant couples enrolled in a SW-IUI program and followed up 367 Italian women. We computed pregnancy, live birth, and multiple delivery rates and assessed the women's postinsemination HIV status.
Results
The retrospective analysis included 635 couples (2113 SW-IUI cycles): 41% of the women (95% confidence interval [CI], 37–45%) had a live birth (per-cycle live birth rate 13%; 95% CI, 11–14%). HIV status after SW-IUI was negative when available but unknown for 26% of the women: missing HIV status was not associated with correlates of HIV risk. The follow-up study included 367 couples (1365 cycles): 47% of the women (95% CI, 42–52%) had a live birth (per-cycle rate 14%; 95% CI, 12–16%). Ascertainment of postinsemination HIV status was complete and confirmed no HIV transmission attributable to SW-IUI. The upper 95% confidence limit of the HIV transmission rate was 1.8 per 1000 cycles in the retrospective analysis and 2.7 per 1000 cycles in the follow-up study.
Conclusion
SW-IUI appears to be a safe and effective method for achieving pregnancy in HIV-discordant couples in which the man is HIV infected.
Human immunodeficiency virus (HIV)-affected couples may need assisted reproduction to avoid sexual transmission of the virus or to overcome infertility.
American College of Obstetricians and Gynecologists ACOG Committee Opinion no. 255 HIV: Ethical Guidelines for Obstetricians and Gynecologists, April 2001.
support fertility services for HIV-discordant couples. The Centers for Disease Control and Prevention (CDC) recommends that reproductive counseling be noncoercive and supportive of patient decisions.
The ASRM recently issued recommendations that fertility clinics make fertility treatments aimed at reducing the risk of transmission more easily accessible to couples who live with HIV.
Risk avoidance through conception with donor sperm or adoption may not be acceptable or accessible to many couples. Risk-reduction strategies that may enable couples to conceive their biological children include semen washing (SW) followed by intrauterine insemination (IUI) and in vitro fertilization (IVF) followed by embryo transfer. Early semen-processing techniques did not yield virus-free spermatozoa and 1 documented case of seroconversion led the CDC to recommend against exposing an HIV-negative woman to her HIV-infected partner's semen.
Today assisted conception offered to HIV-discordant couples in the United States primarily is based on IVF with intracytoplasmic sperm injection (IVF-ICSI).
Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.
Incomplete follow-up, however, has been a source of uncertainty in previous studies. We conducted this study to improve follow-up of a cohort of couples treated in Milan, Italy, between 1989 and 2005.
Materials and Methods
The study comprised a retrospective review of patient records from a program based at the San Paolo University Hospital and the Studio Semprini clinic and a follow-up study of couples in Italy who attended the program. The protocol was approved by the Ethics Committee of the Local Health Agency of the City of Milan and by the CDC Institutional Review Board.
Semen washing includes centrifugation with silica-based discontinuous density gradient, double washing and centrifugation, and sperm swim-up (Figure 1).
In laboratory conditions, the technique reduces the HIV titer by 1000-fold so that washed motile sperm is not infectious to peripheral blood lymphocytes.
Anderson DJ, Politch JA, Oneta M, Tucker L, Semprini AE. Efficacy of conventional semen processing techniques in separation of motile sperm from HIV-1 and HIV-1 host cells. Presented at the 48th Annual Meeting of the American Fertility Society, New Orleans, LA: 1992; [abstract P-213, p. 107-8].
Detection of human immunodeficiency virus-1 RNA and DNA by extractive and in situ PCR in unprocessed semen and seminal fractions isolated by semen-washing procedure.
Insemination with isolated and virologically tested spermatozoa is a safe way for human immunodeficiency type 1 virus-serodiscordant couples with an infected male partner to have a child.
At enrollment in the program, women were required to provide documentation of a negative HIV test within the previous 30 days. Women and their partners were evaluated for genital tract infections and infertility and treated as indicated. Women in fertile couples were offered SW-IUI, whereas IVF was used if indicated by infertility or if the motile sperm count after SW was below 1.5 × 106/mL. All women were asked to undergo HIV serologic testing quarterly for a year after the last SW-IUI cycle.
As part of routine care, clinic staff inquired about missing HIV test results by telephone, probing as much as possible the veracity of the report by asking specific questions about the clinic or laboratory at which the test was performed, the reasons for not sending the test result in, and broadly inquiring into the health of the woman and her male partner.
From the clinic roster, 811 couples who were not currently undergoing treatment at the time of the research participated in the program between July 1, 1989, and April 30, 2005. For the retrospective analysis, we excluded couples in which the man was not HIV infected, who had never completed an SW-IUI cycle, or whose charts were missing. Deidentified data obtained from these couples included demographic characteristics, an HIV-related medical history, a fertility profile of the couple, assisted conception treatment and its outcome, and the postinsemination HIV status of the woman.
Evidence of HIV status consisted of an HIV-antibody test dating 90 or more days after the last SW-IUI cycle; a written note from a follow-up call made by clinic staff; or a new assisted conception cycle (eg, IVF-ICSI) 90 or more days after the last SW-IUI cycle. Women with missing HIV status after the last SW-IUI were compared with those with known status with respect to demographics, medical history, HIV risk behaviors, history of participation in the program, and immune compromise and history of HIV treatment of the man.
For the follow-up study, the same 811 couples were potentially considered for inclusion. However, in addition to the exclusion criteria for the retrospective analysis, the follow-up study also excluded women whose charts contained inadequate tracing information or whose current address or telephone number could not be identified after following up 50 possible leads, whose residence address was not in Italy, who could not speak Italian or English, or whose partner objected to the woman's participation.
The physician who administered treatment initiated recruitment by telephone, and study staff made a second call to explain study procedures and obtain informed consent. Both partners were asked to consent to medical record review and to a telephone interview. Women were asked to provide evidence of, or at least tell about, their postinsemination and current HIV status. Women who refused to participate (nonparticipants) were probed to ascertain whether their refusal was due to HIV transmission. The institutional review board allowed analysis of limited data from women who could not be reached for recruitment (untraced) and from nonparticipants to assess whether these groups were at a higher risk of HIV acquisition than were follow-up participants.
The objectives of data analysis were to describe the characteristics of couples included in the retrospective analysis or in the follow-up study by computing univariate statistics and frequency distributions; to assess the effectiveness of SW-IUI by computing pregnancy, live birth rates, and multiple delivery rates; to assess the safety of SW-IUI by summarizing the available evidence on the postinsemination HIV status of the women; and to evaluate the correlates of the missing HIV status.
A Student t test and χ2 statistics evaluated the significance of differences in means and frequency distributions. Ninety-five percent confidence intervals (CIs) for rates and proportions were computed using exact binomial or Poisson distribution tests, as appropriate. Logistic regression was used to evaluate multiple potential determinants of missing HIV status in the retrospective analysis and to compare follow-up participants with untraced women. Odds ratios (ORs) and their CI were computed from the estimates of the logistic regression coefficients and their variances.
Results
Among the 811 couples who participated in the program during 1989-2005 and were not undergoing treatment at the time of this research project, 635 eligible couples who underwent 2113 SW-IUI cycles contributed data for the retrospective analysis (Figure 2). Of 472 eligible couples, 367 couples who underwent 1365 SW-IUI cycles participated in the follow-up study.
FIGURE 2Disposition of patients attending SW-IUI program in Milan, Italy, 1989-2005
In the retrospective analysis, the average age was 31 and 34 years for the men and women, respectively (Table 1). Of 635 couples, 525 (83%) resided in Italy. Male partners had acquired HIV mainly through injection drug use (70%) or unprotected intercourse (18%). The average number of SW-IUI cycles was 3.3 (range, 1–17). Many couples (53%) reported unsafe sex before entering the program, even after the partner was diagnosed with HIV (25%); 15% had pregnancies and 6% had children with their HIV-positive partner. Low CD4 counts at program entry (<200 cell/mm3) were reported in 14% of the male partners, and only 23% were on highly active antiretroviral treatment (HAART) at the time of the last SW-IUI cycle (Table 1).
TABLE 1Characteristics of study participants
Characteristic
Women in retrospective analysis (n = 635) Mean (median)
Follow-up participants were similar to the subjects in the retrospective analysis but were only Italian residents (by design); had more SW-IUIs (mean, 3.8; range, 1–14); and were more often lacking information on the man's HIV acquisition, baseline CD4 count, and HAART at the last SW-IUI cycle (Table 1). As compared with follow-up participants, untraced women joined the program in earlier years (P < .001), left it earlier (P ≤ .001), were more likely to have male partners who acquired HIV mainly through injection drug use (P = .01), had fewer SW-IUI cycles (average 3.4 vs 3.8) (P = .05), and were less likely to have had a male partner on HAART at last SW-IUI cycle (P = .01) (Table 1).
In the retrospective analysis, 16% of the SW-IUI cycles resulted in pregnancy (95% CI, 15–18%), and 13% resulted in a live birth (95% CI, 11–14%) (Table 2). The cumulative per-woman pregnancy and live-birth rates were 48% (95% CI, 44–52%) and 41% (95% CI, 37–45%), respectively. The multiple delivery rate was 8% (95% CI, 5–12%). In the follow-up study, the pregnancy and live birth rates among SW-IUI cycles were 17% (95% CI, 15–19%) and 14% (95% CI, 12–16%); the cumulative per-woman pregnancy and live-birth rates were 53% (95% CI, 48–59%) and 47% (95% CI, 42–52%), respectively; and the multiple delivery rate was 5% (95% CI, 3–9%).
TABLE 2Pregnancies and live birth deliveries following SW-IUI
No cases of HIV seroconversion were recorded among women included in the retrospective analysis. Evidence of negative HIV status was available for 1899 (90%) SW-IUI cycles (test result on file: 68%; clinician's notation in chart: 18%, other: 4%) (HIV status was unknown 90 days after 214 SW-IUI cycles [10%] performed in 162 women [26%]). On the basis of the cycles with known postinsemination HIV status, the estimate of the HIV transmission rate was zero, and its upper 95% confidence limit was 1.8 per 1000 cycles.
The strongest predictor of missing HIV status in the retrospective analysis was the country of residence: the evidence was missing in 71% of non-Italian residents and 16% of Italian residents (P < .001; OR, 9.2; 95% CI, 5.2–16.3) (Table 3). HIV status was missing more often among couples who had less than 5 SW-IUI cycles than among couples who had 5 or more cycles (P ≤ .01; OR, 2.3; 95% CI, 1.2–4.2). HIV status was missing for 90% of women whose pregnancy status was unknown after the last SW-IUI cycle, 23-32% of women who did not achieve a pregnancy or had a biochemical pregnancy/early pregnancy loss, and 15% of women who had 1 live birth or more (P = .004).
TABLE 3Correlates of missing HIV status after the last SW-IUI procedure, retrospective analysis
Test of the null hypothesis of no association with lack of missing HIV status, from a logistic regression model including all independent variables displayed as well as the following nonsignificant independent variables: risk of HIV transmission by the man (on the basis of low CD4 count or high viral load and no HAART at entry), man infected through injection drug use, years of abstinence from injection drug use prior to program entry, sperm count after SW at last SW-IUI cycle, year of first visit, and year of last SW-IUI.
Variable
n
(%)
n
(%)
Number of cycles
1–4
142
(31)
321
(69)
.01
≥5
20
(12)
152
(88)
Italian resident
Yes
84
(16)
441
(84)
< .001
No
78
(71)
32
(29)
Outcome for last SW-IUI cycle
No pregnancy
70
(23)
238
(77)
Biochemical/pregnancy loss
13
(32)
28
(68)
.004
Live birth
36
(15)
202
(85)
Unknown
43
(90)
5
(10)
Mode of HIV acquisition by male partner
Injection drug use
85
(19)
355
(81)
.08
Other
77
(39)
118
(61)
HAART, highly active antiretroviral treatment; HIV, human immunodeficiency virus; SW-IUI, semen washing with intrauterine insemination.
Semprini. Conception for HIV-discordant couples. Am J Obstet Gynecol 2013.
a When evidence about HIV status after the last SW-IUI was available, it always indicated no transmission of HIV infection to the woman;
b Test of the null hypothesis of no association with lack of missing HIV status, from a logistic regression model including all independent variables displayed as well as the following nonsignificant independent variables: risk of HIV transmission by the man (on the basis of low CD4 count or high viral load and no HAART at entry), man infected through injection drug use, years of abstinence from injection drug use prior to program entry, sperm count after SW at last SW-IUI cycle, year of first visit, and year of last SW-IUI.
These differences were also significant among Italian residents (data not shown). Correlates of the risk of HIV transmission (viral load, CD4 cell count at entry into the program, on HAART at time of last SW-IUI, years of abstinence from drug use in the man, history of drug use in the woman, history and length of unprotected sex behavior prior to program entry, and year of enrollment in the program) were not associated with missing HIV status in multiple regression analyses.
Evidence of negative HIV status was available for all of the 367 follow-up participants and for the corresponding 1365 SW-IUI cycles. The HIV transmission rate was zero (upper 95% confidence limit 2.7 per 1000 cycles).
We investigated the concern that untraced women and nonparticipants could conceal events of HIV transmission after SW-IUI. A negative HIV test result was on file for 22 of 72 eligible, untraced women (31%). As reported above, they were not different from participants with respect to correlates of risk of HIV transmission in multiple regression analyses. The male partners of untraced women were less frequently on HAART at the time of the last SW-IUI, but this association reflected the large proportion of couples in this group whose participation in the program occurred before HAART became available and was no longer significant after adjusting by year of entry into the program and year of last SW-IUI. All nonparticipants (n = 33) declared that their refusal was not due to HIV acquisition after SW-IUI.
Although no seroconversions related to program participation were documented, additional data were collected during the follow-up study on behaviors and events that occurred outside participation in the program. These follow-up data indicated that 73 participants (19.6%) attempted conception through unprotected intercourse with their HIV positive partner, either before joining or after leaving the program, and 59 (15.9%) reported that they had children following unprotected intercourse. One woman reported seroconversion following such a conception attempt, 4 years after leaving the program (she was HIV negative 1 year after the last SW-IUI).
Comment
People with HIV can lead healthy lives and raise children
Antiretroviral Therapy Cohort Collaboration Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.
: it is important that they have options for conceiving safely. SW-IUI is simple and is likely to be much less expensive than IVF. The 1990 CDC recommendation against semen washing was based on the seroconversion of a woman whose partner's semen was processed by a method that did not reliably separate spermatozoa from seminal plasma and leukocytes.
The present study evaluates methods that were developed during this same period of time in Italy to yield HIV-free motile spermatozoa.
The practice of assisted reproduction for HIV-discordant couples in Europe and the United States has since diverged. In Europe, SW-IUI became routine because reports repeatedly confirmed no seroconversion events.
In the United States, SW-IUI never became part of mainstream patient care. One group in New York obtained ethics board approval for IVF-ICSI followed by embryo transfer.
Compared with no intervention, IVF-ICSI should greatly reduce the risk of HIV transmission, and no seroconversion has occurred in 181 couples who underwent 420 IVF-ICSI cycles.
Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.
The method, however, is expensive and carries the risks of assisted reproductive technology (ART): in the New York cohort, 41% of the deliveries were associated with multifetal gestation and 74% were preterm. Our findings suggest that SW-IUI may provide a safer and less expensive alternative for fertile couples who are seeking protection from the sexual transmission of HIV. Recently ASRM and ACOG have expressed their support for the provision of fertility services for HIV-discordant couples, and in 2008, the State of California enacted legislation enabling the provision of such services.
The CDC funded this study to provide evidence for a possible review of the 1990 recommendation. Neither the retrospective review of the cohort of 635 women who participated in the program nor the follow-up study of 367 Italian couples identified any seroconversions attributable to SW-IUI. This finding is statistically compatible with a transmission rate as low as 1.8 or 2.7 per 1000 cycles (the upper limits of our estimates), depending on the analysis, and strengthens the published evidence.
SW-IUI was effective, with a per-cycle pregnancy rate of 16% and a cumulative per-woman live birth rate of up to 47%. These rates are comparable with those achieved using IUI with infertile couples
Of 255 live birth deliveries, only 20 (8%) were multiple, and SW-IUI seems safer than IVF with respect to the risk of adverse pregnancy outcomes.
The most important limitation of this study is that we did not have complete ascertainment of HIV status for all SW-IUI cycles, and therefore, we cannot exclude the possibility that HIV transmission occurred. The postinsemination HIV status was available for 90% of SW-IUI cycles and 74% of women in the retrospective analysis (100% of follow-up study participants). These ascertainment rates are high but cannot definitely exclude a rare outcome. The strongest predictor of missing HIV status was residence in a country other than Italy: distance may have interfered with patient follow-up.
Other strong predictors were fewer SW-IUIs, a shorter time in the program, and failure to achieve a pregnancy. Correlates of HIV risk were not associated with missing HIV status. Untraced women tended to have been enrolled in the treatment program in early years when effective antiretroviral treatment was not available but were otherwise similar to study participants with respect to HIV risk. Nonparticipants clarified that their refusal to participate was not because they had acquired HIV after SW-IUI. Thus, it seems unlikely that HIV transmission occurred in women with unknown postinsemination HIV status.
An additional limitation was that this study had limited power. Because the risk of HIV transmission is low (1-2 per 1000 acts of unprotected intercourse),
to demonstrate protection. Thus, taken in isolation, the present report may not be sufficient to document the protective effect of SW-IUI. However, collectively, the published reports on the safety of SW-IUI
cover more than 5400 cycles with no HIV transmission, reducing the upper 95% confidence limit of the HIV transmission rate to 0.67 per 1000 cycles.
The results pertain to the largest and earliest cohort of HIV-discordant couples who have conceived through SW-IUI and include many couples who participated before the advent of HAART and viral load assessment, when the risk of transmission in the absence of intervention may have been higher. This strengthens the evidence about SW-IUI safety. It is reassuring that intense follow-up achieved complete ascertainment of HIV status without uncovering seroconversions.
Follow-up data also highlighted the importance of safe conception for HIV-discordant couples by documenting HIV transmission to a woman who attempted conception by unprotected intercourse after leaving the program without HIV infection. Reproductive desire can overcome the fear of transmission.
Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.
there still may be some risk of HIV transmission. In a recent randomized clinical trial, which demonstrated that early initiation of antiretroviral therapy reduces the risk of sexual transmission of HIV compared with delayed initiation, the 1 transmission in the early-therapy group was from a man to his uninfected female partner.
Thus, viral transmission is more likely to occur when the seminal viral load is high and the woman's genital tract is receptive. SW-IUI can reduce the viral load to undetectable levels every time that the woman needs to be exposed, thus eliminating variation in risk associated with changes in semen.
Finally, SW-IUI should be part of a comprehensive reproductive care strategy for the HIV-discordant couple, in which the risk of transmission is synergistically reduced by managing the HIV-positive man and his response to antiviral treatment,
by detecting and treating genital tract infections in both partners, by increasing awareness of fertility, by detecting and managing infertility, and by providing treatment options ranging from SW-IUI to ART.
In conclusion, this study provides reassuring evidence about the safety and effectiveness of SW-IUI for HIV-discordant couples who wish to conceive. If this method is adopted in the United States, it would be prudent to establish a surveillance program to ensure that the laboratories adhere to performance standards and to monitor patient outcomes.
Acknowledgments
The study staff expresses its gratitude to Dr Maria Gallo (CDC) for her valuable scientific input, to Ms Jennifer Legardy-Williams (CDC) for her methodological and administrative support, to Ms Elena Parisi for the administrative and logistic support, to Mr Claudio Innocenti for his important contribution to the study datasets development and management, to Professor Ferruccio Osimo for his supervision of the formative phase and development of study tools, and to the counselors Alessia Bajoni and Elisabetta Mangano for their skilled contribution to participant enrollment and support in the follow-up study.
References
Sunderam S.
Hollander L.
Macaluso M.
et al.
Safe conception for HIV discordant couples through sperm-washing: experience and perceptions of patients in Milan, Italy.
Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.
Anderson DJ, Politch JA, Oneta M, Tucker L, Semprini AE. Efficacy of conventional semen processing techniques in separation of motile sperm from HIV-1 and HIV-1 host cells. Presented at the 48th Annual Meeting of the American Fertility Society, New Orleans, LA: 1992; [abstract P-213, p. 107-8].
Detection of human immunodeficiency virus-1 RNA and DNA by extractive and in situ PCR in unprocessed semen and seminal fractions isolated by semen-washing procedure.
Insemination with isolated and virologically tested spermatozoa is a safe way for human immunodeficiency type 1 virus-serodiscordant couples with an infected male partner to have a child.
This study was supported by Contraceptive Research and Development, Eastern Virginia Medical School, subproject (CSA-01-388) under a Cooperative Agreement with the United States Agency for International Development (grant HRN-A-00-98-00020-00 ), which in turn receives funds for AIDS research from an interagency agreement with the Division of Reproductive Health, Centers for Disase Control and Prevention.
The views expressed herein are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, United States Agency for International Development, or Contraceptive Research and Development.
Dr Macaluso is currently Director, Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. Dr Duerr is currently Director of Scientific Affairs, HIV Vaccine Network, Fred Hutchison Cancer Research Center, Seattle, WA.
The authors report no conflict of interest.
Reprints not available from the authors.
Cite this article as: Semprini AE, Macaluso M, Hollander L, et al. Safe conception for HIV-discordant couples: insemination with processed semen from the HIV-infected partner. Am J Obstet Gynecol 2013;208:402.e1-9.
In “Safe conception for HIV-discordant couples: Insemination with processed semen from the HIV-infected partner,” Semprini et al1 document the safety of semen washing with intrauterine insemination (SW-IUI) from the largest cohort to-date. These data have the potential to significantly alter the landscape of reproductive health care for such couples in the US.
We read with great interest the article by Semprini et al1 concluding that semen washing with intrauterine insemination (SW-IUI) appears to be a safe and effective method for achieving pregnancy in human immunodeficiency virus (HIV)-discordant couples in which the man is HIV infected.
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