Augusto E. Semprini

Effectiveness of semen washing to prevent human immunodeficiency virus (HIV) transmission and assist pregnancy in HIV-discordant couples: a systematic review and meta-analysis

OBJECTIVEnTo evaluate the effectiveness of semen washing in human immunodeficiency virus (HIV)-discordant couples in which the male partner is infected.nnnDESIGNnSystematic review and meta-analysis.nnnSETTINGnNot applicable.nnnPATIENT(S)nForty single-arm open-label studies among HIV-discordant couples that underwent intrauterine insemination (IUI) or in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) using washed semen.nnnINTERVENTION(S)nSemen washing followed by IUI, IVF, or IVF/ICSI.nnnMAIN OUTCOME MEASURE(S)nnnnPRIMARY OUTCOMEnHIV transmission to HIV-uninfected women; secondary outcomes: HIV transmission to newborns and proportion of couples achieving a clinical pregnancy.nnnRESULT(S)nNo HIV transmission occurred in 11,585 cycles of assisted reproduction with the use of washed semen among 3,994 women. Among the subset of HIV-infected men without plasma viral suppression at the time of semen washing, no HIV seroconversions occurred among 1,023 women after 2,863 cycles of assisted reproduction with the use of washed semen. Studies that measured HIV transmission to infants reported no cases of vertical transmission. Overall, 56.3% of couples (2,357/4,184) achieved a clinical pregnancy with the use of washed semen.nnnCONCLUSION(S)nSemen washing appears to significantly reduce the risk of transmission in HIV-discordant couples desiring children, regardless of viral suppression in the male partner. There are no randomized controlled studies or studies from low-income countries, especially those with a large burden of HIV. Continued development of lower-cost semen washing and assisted reproduction technologies is needed. Integration of semen washing into HIV prevention interventions could help to further reduce the spread of HIV.

Perinatal Outcome in HIV-Infected Pregnant Women

We have observed 74 HIV-seropositive and 48 HIV-seronegative drug-addicted women and 22 HIV-seropositive nondrug-addicted pregnant women during pregnancy and we report their perinatal outcome. 8 out of 96 HIV-seropositive patients had hematological signs of immunodeficiency and 2 of these patients were symptomatic belonging to CDC class III. We recorded 2 early and 3 late spontaneous abortions, no intrauterine fetal death and 3 neonatal deaths. Seropositive patients had 3 malformed babies, seronegative patients had 1. All these women had a high incidence of premature delivery and intrauterine fetal growth retardation: seropositive patients had a higher incidence of fetuses small for gestational age and a lower incidence of preterm delivery compared to seronegative patients, but the difference was not statistically significant. The incidence of malformation was comparable to the general population: 3 malformed babies were born to HIV-positive drug-addicted mothers, and 1 to a seronegative drug-addicted mother. These findings do not support the hypothesis of a direct detrimental effect of HIV on perinatal outcome. Consequences of fetal exposure to maternal HIV infection involve mostly postnatal life and development of acquired immunodeficiency.

Effect of Prednisone and Heparin Treatment in 14 Patients with Poor Reproductive Efficiency Related to Lupus Anticoagulant

In women with a previous intrauterine fetal death related to lupus anticoagulant (LAC), we studied the effect of prednisone and calcieparine treatment to enable longer intrauterine life, increased fetal growth and increased survival rate. LAC was determined by the kaolin clotting time and was associated with elevated levels of antinuclear and anticardiolipin antibody in 42% and 21% of the cases, respectively. 14 women entered the study; they had a past history of 27 pregnancies, with only 1 small-for-gestational age (SGA) liveborn. The mean gestational age at the time of fetal death was 30 +/- 4 weeks. During index pregnancies, we observed 2 miscarriage, 9 liveborns (6 of appropriated gestational weight, 3 SGA) and a mean gestational age of 35 +/- 3 weeks. The mean decrease in fetal weight from the 50th percentile in previous pregnancies was 44%, and with treatment this was reduced to 12%. All these differences were statistically significant. We conclude that prednisone and heparin treatment can improve reproductive prognosis in fertile patients with LAC.

Non-invasive tool for foetal sex determination in early gestational age

Summary.u2002 Free foetal DNA in maternal blood during early pregnancy is an ideal source of foetal genetic material for non‐invasive prenatal diagnosis. The aim of this study was to evaluate the use of free foetal DNA analysis at early gestational age as pretest for the detection of specific Y‐chromosome sequences in maternal plasma of women who are carriers of X‐linked disorders, such as haemophilia. Real‐time quantitative PCR analysis of maternal plasma was performed for the detection of the SRY or DYS14 sequence. A group of 208 pregnant women, at different gestational periods from 4 to 12u2003weeks, were tested to identify the optimal period to obtain an adequate amount of foetal DNA for prenatal diagnosis. Foetal gender was determined in 181 pregnant women sampled throughout pregnancy. Pregnancy outcome and foetal gender were confirmed using karyotyping, ultrasonography or after birth. The sensitivity, which was low between 4th and 7th week (mean 73%), increased significantly after 7+1th weeks of gestation (mean 94%). The latter sensitivity after 7+1th week of gestation is associated to a high specificity (100%), with an overall accuracy of 96% for foetal gender determination. This analysis demonstrates that foetal gender determination in maternal plasma is reliable after the 9th week of gestation and it can be used, in association with ultrasonography, for screening to determine the need for chorionic villus sampling for prenatal diagnosis of X‐linked disorders, such as haemophilia.

Treatment with interferon for genital HPV in HIV-positive and HIV-negative women

The administration of interferons can be resorted to, either on its own or in combination with physical destruction methods, when the extent of genital HPV is widespread. Extensive genital HPV involvement is often seen in HIV-positive patients as a consequence of their immunodeficiency. The extension of these lesions may invalidate treatment by physical destruction, while an underlying immunodeficiency renders interferon therapy less efficacious. We studied HIV-positive and HIV-negative patients with a similar HPV involvement of their genital tract and compared the effectiveness of systemically administered alpha 2b and beta interferons in clearing HPV. Our results confirm that interferon therapy will cure most patients with extensive genital HPV when they are HIV-negative. HIV-positive patients with CD4 counts over 400 lymphocytes/mm3 may expect a similar cure rate, but this halves when this critical threshold is crossed. In these severely immunodeficient patients repeated courses of interferon therapy alone or in combination with physical destruction methods may be required to cure HPV infection.

Consensus statement: supporting safer conception and pregnancy for men and women living with and affected by HIV

Safer conception interventions reduce HIV incidence while supporting the reproductive goals of people living with or affected by HIV. We developed a consensus statement to address demand, summarize science, identify information gaps, outline research and policy priorities, and advocate for safer conception services. This statement emerged from a process incorporating consultation from meetings, literature, and key stakeholders. Three co-authors developed an outline which was discussed and modified with co-authors, working group members, and additional clinical, policy, and community experts in safer conception, HIV, and fertility. Co-authors and working group members developed and approved the final manuscript. Consensus across themes of demand, safer conception strategies, and implementation were identified. There is demand for safer conception services. Access is limited by stigma towards PLWH having children and limits to provider knowledge. Efficacy, effectiveness, safety, and acceptability data support a range of safer conception strategies including ART, PrEP, limiting condomless sex to peak fertility, home insemination, male circumcision, STI treatment, couples-based HIV testing, semen processing, and fertility care. Lack of guidelines and training limit implementation. Key outstanding questions within each theme are identified. Consumer demand, scientific data, and global goals to reduce HIV incidence support safer conception service implementation. We recommend that providers offer services to HIV-affected men and women, and program administrators integrate safer conception care into HIV and reproductive health programs. Answers to outstanding questions will refine services but should not hinder steps to empower people to adopt safer conception strategies to meet reproductive goals.

The changing HIV epidemic in Italian pregnant women.

OBJECTIVEnTo describe changes in the characteristics of HIV-pregnant women in Italy and the impact of strategies for prevention of HIV vertical transmission.nnnSTUDY DESIGNnSince 1985, HIV-infected women and their children are followed in 23 European centres in the European Collaborative Study (ECS), according to a standard protocol. Eight Italian Obstetric units participating in the ECS enrolled 815 patients.nnnRESULTSnOverall use of zidovudine to reduce HIV vertical transmission has increased significantly since 1994 and between 1995 and 1997, 57% of Italian women were treated. However, 27% of babies received the infant component of the 076 regimen. Over the years, age at delivery has increased and their CD4 count at delivery decreased, most likely reflecting heterosexually infected women with a longer duration of infection. The increasing rate of elective caesarean section (42%) is not related to maternal, foetal or obstetrical indications, but its use as an intervention to reduce HIV vertical transmission.nnnCONCLUSIONSnThe identification of HIV-infected women during pregnancy or before delivery ensures the appropriate management of the woman and her child, and clinicians should be aware of the increasing number of women with heterosexual acquisition of HIV-infection who may be less easily identified.

Hepatitis C in Pregnancy and Mother-to-Infant Transmission of HCV

Abstract Pregnancy is not contraindicated to women infected with HCV and HCV infection does not adversely affect pregnancy. The risk of mother-to-infant transmission of HCV is approximately 5%, but may be higher in children born to mothers with HCV/HIV co-infection. Transmission of infection is usually restricted to mothers who are HCV-RNA positive. Higher HCV-RNA levels seem to be associated with a greater risk, but a specific cut-off value predicting transmission cannot be defined. Interferon and ribavirin are contraindicated during pregnancy. There is no evidence that Caesarean delivery may reduce risk of vertical infection compared to vaginal delivery. Caution should be recommended in using invasive procedures (amniocentesis, villocentesis, and funicolocentesis), which may potentially expose the foetus or the neonate to the infected maternal blood. Avoiding foetal scalp monitoring and prolonged labour after rupture of membranes may reduce the risk of vertical transmission of HCV. Breastfeeding appears to be safe and is not contraindicated. Infected children usually progress to chronic disease with a benign course, at least initially. Longitudinal studies are needed to determine the long-term natural history of vertical HCV infections. Interferon plus ribavirin combination has been shown to be safe and effective in treating hepatitis C during childhood. Vaccinations against both hepatitis A and hepatitis B are highly recommended to children infected with HCV.

Reproductive care in human immunodeficiency virus serodiscordant couples with haemophilia.

Dear Editor, n nHaemophilia is the most common hereditary bleeding disorder: it is spread worldwide, without ethnic or geographical limitations, and remains a life-threatening and often disabling condition. A typical patient with severe haemophilia develops spontaneous haemorrhages into joints, muscles or soft tissues. Until 1985, the mainstay of the treatment of haemophilia was repeated infusions of plasma-derived products. Prior to the development of viral inactivation procedures in the mid-1980s, virtually all haemophiliac patients who had previously received large pool plasma-derived factor concentrates were infected with hepatitis C virus. Moreover, 15% of haemophiliacs were also infected with human immunodeficiency virus (HIV)1. The development and introduction of highly active anti-retroviral therapy (HAART) have transformed the lives of haemophiliacs infected with HIV and redefined this as a chronic, as opposed to fatal, infection. Haemophilic patients infected with HIV lead relatively normal lives and, as a consequence of this improvement in wellbeing, an increasing number of couples consider the possibility of having a child. Reproductive assistance to HIV serodiscordant couples, in which the male partner is HIV-positive and the female partner is negative, could give a significant contribution to the prevention of viral transmission. In such couples, it has been estimated that the HIV-negative female partner has a 0.1–0.5% risk of acquiring HIV per act of unprotected intercourse, considering couples in stable monogamous relationship, not abusing intravenous drugs or participating in any other high-risk activities2. HIV-positive subjects who wish to avoid the risk of transmitting HIV to their uninfected partners, have various possibilities when considering having a family. They may decide to remain childless or to use non-biological methods, such as insemination using donor sperm or adoption. These couples may also opt for techniques of assisted conception using specialised semen preparations, such as sperm washing. The use of this procedure is based on the observation that HIV is present as free virus in seminal plasma and as cell-associated virus in leucocytes, but does not infect spermatozoa3. An HIV-negative female partner can be inseminated with her HIV-positive partner’s sperm, after this virus elimination procedure. n nWe report our experience on 17 HIV-discordant couples referred to the Haemophilia Centre of Milan for reproductive assistance, for whom the sperm washing method was used to remove HIV DNA and RNA from the ejaculate. n nAll couples underwent complete fertility screening to define the optimal reproductive technique to achieve pregnancy after sperm washing. Both members of the couple were informed of a minimal residual risk of HIV transmission and signed written informed consent. All haemophilic patients were on anti-retroviral therapy at the time of semen analysis. The male patients had undetectable concentrations of HIV RNA in their blood plasma (range 50–200 copies/mL) and stable CD4+ T-cell counts for the preceding 6 months. Female partners were tested for HIV and were seronegative. n nThe semen samples were processed by centrifuging in a 40–80% density gradient to separate motile spermatozoa from non-sperm cells. After centrifugation, the supernatant was removed and the sperm pellet was recovered and re-suspended in fresh medium and centrifuged twice before preparation of a final swim-up. As a procedure quality control, an aliquot of washed sperm (approximately 100 μL) was tested for detectable HIV RNA. The assay detection limit was 50 RNA copies/mL. The remaining washed sperm was stored at 4 °C for 22 hours and used, if the HIV test was negative, for reproductive procedures. n nIn the absence of infertility factors in the female partner and with good seminal quality after sperm washing, couples underwent up to three cycles of intrauterine insemination (IUI) with washed spermatozoa. Extracorporeal fertilisation, with standard in vitro fertilisation (IVF) procedures or by direct intracytoplasmic sperm injection (ICSI) into the oocyte, was selected forthwith when required by the couple’s fertility parameters or used when three cycles of IUI failed to achieve a pregnancy. n nResults for IUI, IVF and ICSI using washed sperm in our series of 17 treated patients are shown in Table I. n n n nTable I n nAssisted reproductive techniques and pregnancy outcomes in HIV-discordant couples. n n n nFour couples (23.5%) underwent IUI. The mean age of the female partners was 32.5 years (range, 30 to 34 years). Three singleton pregnancies were achieved and were carried to term (75%). n nThe mean age of the 13 women (76.5%) who underwent IVF/ICSI treatment was 34.6 years (range, 27 to 42 years). One of the two women treated with IVF became pregnant; her pregnancy is currently ongoing. Among the 11 women treated with ICSI, 6 clinical pregnancies were achieved (54%): three singletons, one twin and one triplet. Only one singleton was miscarried at the eighth week. n nAll the women who underwent these reproductive procedures were monitored for HIV infection in the third and sixth months after the treatment with washed sperm and they were all negative. The women were tested again after delivery and the results were negative in all cases. All the neonates delivered were healthy and uninfected. n nSperm washing coupled with IUI/ICSI offers haemophiliacs infected with HIV the possibility of becoming fathers without the risk of transmitting the HIV infection to their partners and offspring, showing that providing information on reproductive possibilities should be part of the management of haemophiliacs, enabling them to make the optimal reproductive choice. n nRecently an alternative method, based on the potential role of oral pre-exposure prophylaxis (PrEP) with antiretroviral therapy, has been developed to achieve safe conception in HIV-discordant couples. Research in animal models has provided evidence for the efficacy of PrEP drugs, and has formed the basis for design of human clinical trials4,5. On-going trials will answer many of the outstanding questions about the effects of PrEP drugs, including optimal dosing schedule, route of administration, and efficacy for different types of HIV exposure.

21 Hepatitis C and pregnancy

Publisher Summary This chapter discusses how hepatitis C can affect pregnancy. Hepatitis C during pregnancy offers several challenges in management and therapy. Chronic hepatitis C does not appear to adversely affect pregnancy, delivery, or perinatal health of the mother or newborn. Thus, a woman known to have hepatitis C virus (HCV) infection should not be counseled against becoming pregnant unless she has advanced hepatic disease. Rather, the major issues in management should be to ensure the safety of the pregnancy for mother and child and to reduce the risk of transmission of the virus to the newborn. Counseling before pregnancy and attentive obstetric care can affect both factors favorably. Transmission of hepatitis C can occur during pregnancy, at the time of delivery, or postnatal. The relative roles of each of these times of transmission remain unclear, but most evidence indicates that the peripartum period is most important. Maternal characteristics, such as high levels of HCV RNA in serum or presence of human immunodeficiency virus (HIV) infection, may increase the likelihood of transmission. The role of obstetric factors such as cesarean versus vaginal delivery and the use of monitoring devices and different instruments are still under investigation.