INTRODUCTION — Artificial insemination, the introduction of semen into the vagina, cervix, uterus, or oviduct by means other than sexual intercourse, is one type of assisted reproductive technology (ART). This topic will review use of donor sperm for insemination, also known as therapeutic donor insemination (TDI). Additional content on ART can be found separately:
●(See "In vitro fertilization: Overview of clinical issues and questions".)
●(See "Assisted reproductive technology: Infant and child outcomes".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.
DEFINITIONS — Commonly used terminology includes:
●Artificial insemination – Artificial insemination refers to the introduction of semen into the vagina, cervix, uterus, or oviduct by a means other than sexual intercourse.
●Therapeutic donor insemination (TDI) – When the procedure is performed using sperm from a man other than the patient's partner, it is termed therapeutic donor insemination (TDI) [1-3]. Therapeutic donor insemination (TDI) has been in use longer than any other assisted reproductive technique for treatment for male infertility.
●Non-identified donor – The increased prevalence of nonmedical genetic testing may allow previously "anonymous" sperm donors to be identified. Therefore, the term "anonymous" donor is no longer being used and has been replaced by "non-identified" [4].
INDICATIONS — Historically, TDI was primarily a treatment of male factor infertility. However, the indications for TDI have expanded such that it has become an alternative approach to fertility [4].
The procedure can be considered in the following scenarios:
●Male partner with ejaculatory dysfunction.
●One or both partners are carriers of a heritable disease.
●Serodiscordant for sexually transmissible viral infections in which the female partner wishes to avoid any potential risk of transmission. This is mainly for females who desire to avoid any risk of transmission in a serodiscordant relationship. This could also be mitigated in couples on PREP or those who are routinely taking antiretroviral medications with an undetectable viral load [5].
●Lack of fertilization with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
●Individuals without a male partner or with a transmasculine partner.
●Incompatible red cell antigens (eg, D, Kell) associated with hemolytic disease of the newborn and with a history of a severely affected infant.
●Lack of access (eg, availability, cost, or other) to IVF with ICSI for severe male factor infertility.
Male partner infertility — When the male partner has azoospermia, severe oligospermia, or other severe semen abnormalities resulting in infertility, the main treatment options are: (1) adoption, (2) TDI, (3) ICSI, and (4) remaining childless. Many couples choose to have ICSI with or without testicular biopsy as the initial approach to treatment of infertility due to severe semen abnormalities [6]. However, the high cost of ICSI forces other couples to undergo TDI for financial reasons. (See "Intracytoplasmic sperm injection".)
Heritable disease — The potential for heritable disease in offspring should be considered in couples in whom either one or both partners are affected by the disease or when asymptomatic carrier couples have an affected child. Depending upon the genetics of the disorder, such couples may opt for TDI from a noncarrier or phenotypically normal donor. Preimplantation genetic diagnosis with selection of unaffected blastocytes for implantation and prenatal genetic amniocentesis/chorionic villous biopsy with termination of an affected fetus are other options. These options are only useful when laboratory studies can identify the responsible gene or detect a diagnostic marker. (See "Preimplantation genetic testing".)
Serodiscordance for viral infection — Men who have sexually transmissible viral infections, such as hepatitis C and HIV, and a seronegative partner risk infecting the uninfected partner with their semen [7]. One option for these couples is TDI from an uninfected donor. In one survey of serodiscordant couples, 48 percent of respondents stated they would prefer TDI to timed unprotected intercourse [8]. However, recent studies have shown that the use of sperm washing coupled with assisted reproductive technology (ART; intrauterine insemination [IUI], IVF, ICSI) can be safely utilized in serodiscordant couples to prevent transmission to the uninfected partner [9,10]. There are no reports of HIV seroconversion with use of ART to date [10]. There have yet to be any studies evaluating the opinion of serodiscordant couples on the use of semen washing of the affected partner versus TDI.
Failed ART — TDI can be successful in infertile couples after failure of different testicular sperm retrieval procedures (ie, testicular sperm extraction, microsurgical epididymal sperm aspiration) or after fertilization failure by IVF or ICSI. Three studies have reported that the use of TDI after failed IVF or ICSI is beneficial [11-13]. For example, one study evaluated 45 couples with severe male factor infertility who underwent TDI after failed ICSI. Ninety TDI cycles were completed during the study period and 20 out of the 45 couples (44.4 percent) conceived within four cycles [12]. The pregnancy rate per cycle was 22.2 percent and the live birth rate per cycle was 18.9 percent with an average of 1.5 TDI cycles per couple [12].
Absence of a male partner or with transmasculine partner — In accordance with local guidelines, we provide fertility services to individuals regardless of their marital status, sexual orientation, or gender identity [14]. TDI is commonly used to achieve pregnancy in females without a male partner or whose partner is transmale. In 2019, a US survey-based study using a cohort from the National Survey of Family Growth reported that 46 percent of females who used donor sperm from 1995 to 2017 were unmarried and 43 percent were other than heterosexual [15]. The number of single or lesbian women who perform self-inseminations is unknown. This could possibly be because self-inseminations do not require a physician, and single or coupled patients can do self-inseminations with a known donor's fresh sperm without medical oversight or a physician's order.
CONTRAINDICATIONS — Women with subfertility due to tubal factors, uterine malformations, active pelvic infection, or uncorrected anovulation are not good candidates for donor insemination.
GUIDELINES — Although TDI has been an established medical practice since the early twentieth century, little surveillance or regulation was placed on the practice until 1979, when a landmark survey of TDI practices in the United States was published [16]. The study showed that physicians usually selected the donors, and that most physicians used medical students or hospital residents, while 10 percent used donors from military academies, male partners of patients in their practice, or friends. Screening was often limited and consisted primarily of the physician asking if the donor had any family or personal history of genetic diseases. Only 29 percent of physicians screened donors with biochemical tests other than blood type, and these tests were primarily for communicable diseases. In addition, 50 percent of respondents rejected donors who had a history of a sexually transmitted disease or drug use; 50 to 70 percent attempted to match donors with the recipient's partner in hair color, skin color, eye color, and/or height, while 8 percent did not attempt any donor matching; and nearly one third used multiple donors within a single cycle. Most physicians limited the use of a donor to six pregnancies, while 10 percent used each donor for nine or more pregnancies, and 88 percent had no specific policy regarding the maximum use of a donor. Only one-third kept permanent records regarding donors and children from donor cycles on record.
Since this study, the field of sperm donation has been revolutionized with increased regulation regarding selection criteria and screening for sexually transmitted diseases and genetic disorders. In the United States, the 2021 "Guidance regarding game and embryo donation" provides the most recent detailed recommendations for evaluation of potential sperm, oocyte, and embryo donors, incorporating current information about optimal screening and testing for sexually transmitted infections (including HIV), genetic diseases, and psychological assessments [4]. The document includes information from the US Centers for Disease Control and Prevention, the US Food and Drug Administration, and the American Association of Tissue Banks. In 2014, the Ethics Committee of the ASRM published a report on the interests, obligations, and rights of the [egg or sperm] donor in gamete donation, which was updated in 2019 [17]. A synopsis of these guidelines, and additional information, are described below. Federal regulations for gamete and embryo donation in the United States are available online:
●www.fda.gov/BiologicsBloodVaccines/default.htm
Donor requirements — For ethical reasons, no individual associated with a facility performing the TDI, including the physician, can serve as a donor in that practice.
Donors should be of legal adult age according to their local laws but ideally >21 years old and younger than age 40 years; however, many sperm banks limit the age of their donors to under 35 years. The upper age limit is meant to limit the possibility of aneuploidy or autism related to paternal age, although the data are conflicting. While one study of over 2100 donor insemination cycles reported increasing male age negatively impacted pregnancy rates [18], a larger study of nearly 39,000 women who underwent TDI reported no differences in the live birth or miscarriage rates with increasing age of the donor [19]. (See "Effect of advanced paternal age on fertility and pregnancy".)
A psychological assessment by a qualified mental health professional should be performed on all donors, especially donors <21 years old. The emotional, psychological, and social aspects of sperm donation are addressed as part of this evaluation. Donors are also required to complete questionnaires regarding their attitudes or concerns about transmission of information to or future contact with biological progeny. (See 'Legal and ethical concerns' below.)
Donors are limited to producing 25 births in a population of 800,000 people to minimize the risk of inadvertent consanguinity; however, specific guidelines and limitations vary among countries due to differences in population size and cultural and psychosocial influences [20]. In France, non-identified donor insemination was estimated to be responsible for 0.46 percent of consanguineous births and 0.01 percent of recessive diseases [21]. In fact, consanguineous unions between descendants of non-identified sperm donors were four times less numerous than those between descendants with false paternities.
Donors should also be informed of their responsibility to update their records with future changes in their health status including relevant changes to family history (eg, newly diagnosed genetic disease).
Donors are advised to abstain from ejaculation for 48 to 72 hours prior to producing a specimen [22], and the specimen must be evaluated within one to two hours. Compensation for donation varies according to the sperm bank used; it is generally USD $60 to 100 per specimen. Proven fertility is not essential.
If the recipient prefers directed donation with an identified donor, the donor must still fulfill the above criteria and undergo the screening procedures required of non-identified donors. In addition, legal issues such as parental rights must be addressed prior to insemination. The cost with a identified donor can be more than with a non-identified donor due to the out-of-pocket cost for sexually transmitted infection (STI) testing, semen analysis, and storage fee.
Screening — Donors should be made aware of their responsibility to give accurate medical information. A complete medical history, physical examination (refer to www.sart.org for male donation physical examination form), and routine blood tests including blood type/Rh testing (and possibly a complete blood count, liver function tests, and a chemistry panel) are performed to identify healthy men without evidence of sexually transmitted diseases or known or suspected heritable disease. A complete list of screening questions is available online at "Uniform Donor Application" at www.sart.org.
●Sexually transmitted infection – A complete sexual history is taken to exclude those who might be at high risk for HIV or other sexually transmitted diseases (table 1). Clinicians should be aware of regional guidelines regarding donor exclusion criteria. In the US, evidence of anal intercourse, urethral discharge, genital warts, genital ulcers, intravenous (IV) drug use, disseminated lymphadenopathy, recent nonsterile tattooing or piercings, unexplained oral thrush, jaundice, hepatomegaly, or icterus, and/or rash concerning for smallpox infection or Kaposi sarcoma precludes sperm donation [23]. The US Food and Drug Administration (FDA) also requires that donors be screened for risk factors and evidence of several communicable diseases, including [23]:
•HIV, types 1 and 2 (sometimes HIV group 0)
•Hepatitis B
•Hepatitis C
•Treponema pallidum
•Chlamydia trachomatis
•Neisseria gonorrhea
•Human T-lymphotropic virus (HTLV), types I and II
•Cytomegalovirus (CMV)
•West Nile virus
The full description of the Federal Drug Administration Donor Eligibility: Questionnaire, physical examination, and laboratory testing is available online.
●Genetic evaluation – Potential donors undergo a genetic evaluation. In the United States, the ASRM has published minimum genetic testing for sperm donors [4]. The FDA does not mandate an extensive evaluation for heritable diseases. Most sperm banks advertise that a three-generation family history is taken to evaluate for any heritable diseases. The donor and his first-degree relatives should not have any major Mendelian disorders, major congenital malformations, familial disease with a major genetic component, or known karyotype abnormalities. Although some sperm banks perform a chromosomal analysis, this is not required. The low risk of chromosomal abnormality in these men was illustrated by a large retrospective study that determined the karyotype of over 10,000 normal fertile sperm donors over a 25-year period [24]. Thirty-eight karyotype aberrations (0.37 percent) were diagnosed, including 21 balanced chromosomal rearrangements. The frequency of chromosomal aberrations was similar to that in the general population of newborns.
Genetic testing of high-risk groups is performed; however, ASRM recommends testing for cystic fibrosis, spinal muscular dystrophy, and thalassemia/hemoglobinopathies in all sperm donors [4]. In the United States, guidelines for ethnicity and population-based genetic screening are available from the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG). If test results reveal a heterozygous state, guidelines do not mandate rejection of the donor, but most donor banks state that they screen donors and exclude donors who have any indication of transmitting a higher risk of a hereditary disease. Genetic testing of sperm donors varies among sperm banks; the specific tests performed should be ascertained when using sperm from one of these banks [25].
Expanded carrier screening has become routine within assisted reproductive technology (ART). A 2021 European study found a 17.6 percent rejection rate of donor sperm applicants with use of expanded carrier screening; the most prevalent genetic reasons for exclusion were being carriers for alpha thalassemia, spinal muscular atrophy, and cystic fibrosis [26]. Concerns have been raised about the frequency of genetic traits in the pool of young sperm donors, since these genes may be asymptomatic and thus unknowingly transmitted. Therefore, it is important that intended parents be made aware of the limitations of current genetic testing of prospective donors. A survey of 13 sperm cryobanks within the United States found that 8 out of 13 clinics informed donors of the limitations of the genetic testing [25].
Testing for infection
Risk of infection — A California cryobank reported 47 infections among 48,000 recipients of donor insemination between 1986 and 2004 (1 infection per 1000 recipients) [27]. The rate dropped to 1 in 25,000 for the last 10 years of the study, when semen specimens were processed more intensively. It was not possible to ascertain the proportion of these infections attributable to infection in the semen sample versus recipient factors. The risk of transmission of COVID-19 through cryopreserved donor sperm was determined to be zero [28].
Precautions — Donor sperm samples are quarantined for at least 180 days (six months) after the date of donation to allow testing and retesting of the donors for communicable diseases. The panel of laboratory tests listed above are performed prior to donation or within seven days after recovery of the specimen, after quarantine, and at six month intervals. These tests must be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or CLIA-exempt laboratory. The tests used must be FDA licensed, approved or cleared donor-screening tests.
●If the tests are negative on initial screening, donor samples are prepared for cryopreservation. If the donor tests negative again, after a minimum of 180 days, samples can be released for use.
●If test results are initially positive, the results should be verified and then the individual should be contacted, counseled, and treated according to standard medical practice guidelines.
Although physical separation of specimens that are eligible or quarantined is not required, specimens must be clearly identified and labeled appropriately. Specimens that are ineligible must be physically separated from eligible and quarantined specimens. The FDA requires that donor eligibility records must be maintained for 10 years after the date of distribution, disposition, or expiration, whichever is later. The ASRM recommends that a permanent record of the initial evaluation, test results, and outcomes from each cycle be maintained permanently [4].
Infection-specific protocols — The timing for sperm donation after infection varies based on the type of infection.
●Cytomegalovirus (CMV) – Donors whose serological results are positive for CMV undergo testing to determine whether the infection is likely to be recent or old. Sperm samples from recently infected donors are discarded [29]. Some providers will use sperm samples from men with evidence of remote CMV infection if the recipient is also positive for CMV, but practice patterns vary [4,30]. If the recipient is CMV-negative, she should be counseled that, ideally, she should receive sperm from a CMV-negative donor. However, it is reasonable to allow a patient to choose a donor who is CMV-positive (remote infection), but who meets all other criteria, as long as she provides informed consent indicating that she understands that it is possible to contract CMV from the washed donor sperm. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults" and "Overview of diagnostic tests for cytomegalovirus infection".)
●Zika virus – Based on cases of sexual transmission of the Zika virus, the US Food and Drug Administration (FDA) recommends that sperm donors be considered ineligible if they have been diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors, within the past six months [31]. (See "Zika virus infection: An overview".)
●West Nile virus – According to the FDA, it is recommended that gamete donors with confirmed or suspected West Nile virus infection be deferred for 120 days after the onset of symptoms or diagnosis, whichever is later [4,32-34]. (See "Epidemiology and pathogenesis of West Nile virus infection".)
●Smallpox – Donors who have received smallpox vaccine in the previous eight weeks should be deferred until the vaccination scab spontaneously separates or for 21 days after vaccination, whichever is the later date. Confirmation for scab removal should be performed by physical examination or physical assessment prior to using donor. Intended donors who have experienced complications from the vaccine should wait 14 days after symptom resolution prior to donating. Individuals who have been infected by a recent recipient of the vaccine are advised to defer donation until the vaccine scab has spontaneously separated, three months from the date of vaccination of the vaccine recipient in which the living donor's scab was removed, or until 14 days after resolution of any vaccine-related complications [35]. (See "Variola virus (smallpox)" and "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses".)
●Viral syndromes – Donors with recent significant fever, flu-like illnesses, viral meningitis, encephalitis, or meningoencephalitis should be deferred until healthy [36].
●Ebola – Ebola virus has been detected in semen 199 days from the onset of infection in male survivors [37]. It is not known how long the virus can persist in semen and potentially be transmitted. The World Health Organization has released interim guidelines suggesting that all Ebola survivors "be offered semen testing for Ebola virus RNA by reverse transcription-polymerase chain reaction (RT-PCR) three months after disease onset, and every month thereafter until two consecutive semen specimens collected at least one week apart test negative for Ebola virus RNA" [38].
●Coronavirus – Although guidelines regarding the use of donors who have been infected with COVID-19 are lacking, the risk of coronavirus transmission through cryopreserved donor sperm has been determined to be zero [28]. The use of donor sperm by patients with active COVID-19 infection may vary by clinic. We suggest deferring use of donor sperm from an individual with COVID-19 infection until 14 days after onset of symptoms.
Semen specimen — A single donor produces several semen specimens. Donors produce each specimen in a private room on site. These specimens should meet minimal semen parameters (table 2) (see "Approach to the male with infertility", section on 'Semen analysis'). Studies indicate that donor sperm can result in pregnancy over a wide range of donor sperm concentration, motility, and morphology [39,40].
Proper sperm processing is crucial to successful insemination. Processing for intrauterine insemination separates the sperm from the seminal fluid so that only the most motile, morphologically normal sperm are inseminated. These two characteristics are the most important specimen-related factors affecting outcome [41]. This process is also critical in removing the prostaglandins, inflammatory cells, debris, and proteins from the whole semen specimen, and concentrating the specimen in a small volume. Details of procedure for sperm processing are outside the scope of this topic review.
Unwashed sperm can be used for intracervical insemination or for self-insemination. Pregnancy rates are lower with unwashed sperm, thus washed sperm and intrauterine insemination are typically recommended.
Screening recipients — A routine medical and reproductive history is taken and a general physical examination is performed. Laboratory screening is similar to a standard prenatal panel and includes blood type, Rh factor, antibody screen; testing for immunity to rubella and varicella; testing for active cytomegalovirus infection; and appropriate assessments for the presence of sexually transmitted diseases (HIV, syphilis, gonorrhea, chlamydia, hepatitis B and C) and HTLV type I and II when clinically indicated [4]. ACOG prenatal/preconception guidelines also suggest screening women for cystic fibrosis and other genetic diseases for which they are at risk (see "The preconception office visit"). Theoretically, patients could opt out of this recommendation since the donors are screened for genetic diseases.
Rh-negative women are counseled that they can avoid the risk of hemolytic disease of the fetus and newborn and the need for RhoGAM if they select an Rh-negative donor, but this is generally not a major criterion for donor selection. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management" and "RhD alloimmunization: Prevention in pregnant and postpartum patients".)
Since most pregnancies occur within six cycles, an infertility evaluation should be initiated in woman who have not conceived after six months of inseminations and have not had a previous evaluation. Given the costs of TDI, it makes sense to assess the recipient's fertility even before proceeding with the procedure, especially in women with risk factors for subfertility. As an example, women with risk factors for tubal occlusion should have hysterosalpingography. Screening for ovarian reserve with a day 3 FSH and estradiol testing provides additional potentially prognostic information in women over 40 years of age.
Choosing the donor — Patients can refer to the American Association of Tissue Banks website to find accredited sperm banks. Sperm banks offer varying levels of information about their donors. Some types of information provided include donor profiles (race; height; weight; hair, eye and skin color; educational level; religion; ethnic background), audio tapes, hobbies, baby photos, personality profiles, staff impression reports, essays written by the donor, a report of facial features, and prior history of success in producing a pregnancy [42]. This information may be free; however, some banks will charge for more detailed descriptions or photos. Some banks also offer a consultation service for donor matching.
Documentation — All medical records, including screening evaluations and cycle outcomes, are maintained as permanent records. Informed consent is obtained from the donor to collect sperm and from the recipient for the insemination.
PROCEDURE — The patient lies in a dorsal lithotomy position on a standard gynecologic examination table with feet in stirrups. A speculum is placed in the vagina and the cervix is visualized. Neither local anesthetic nor antibiotic prophylaxis is needed.
The sperm specimen is aspirated into a 1.0 cc syringe. The needle is removed and the plastic syringe is attached to a flexible 18-cm polyethylene catheter (a standard intrauterine insemination catheter) (picture 1). All air is removed from the syringe and catheter and the catheter is inserted through the endocervical canal and should extend 5.5 cm in a typical uterus. The sperm are then injected. Regurgitation of semen from the cervix during the intrauterine insemination (IUI) is not associated with pregnancy outcomes [43]. Mild cramping may occur. After the injection, the catheter is slowly removed and the patient instructed to remain lying flat and still for 15 minutes; however, immobilization for 15 minutes after IUI has not been shown to increase pregnancy rates [44]. A single intrauterine insemination appears to be adequate [45,46]; most observational data from studies of IUI with donor sperm suggest that pregnancy rates are not significantly higher if the procedure is repeated the following day [47-49].
The woman should be able to resume her normal activities upon leaving the office. Subsequent sexual intercourse has not been shown to impede fertilization, but most clinicians suggest abstinence for 24 hours after insemination.
Intrauterine inseminations should be performed by certified health professionals including physicians and nurses who are experienced in administering gynecologic care.
FACTORS AFFECTING SUCCESS — Efforts to improve pregnancy rates have focused upon the number of inseminated sperm, timing of insemination(s), and methods for insemination. The major non-modifiable variables which reduce the likelihood of a successful outcome from the procedure include advanced maternal age and use of frozen sperm.
Maternal age — Maternal age plays a major role in determining a woman's fertility, regardless of the means used to achieve pregnancy (except donor egg) [50] (see "Effects of advanced maternal age on pregnancy"). The effect of advanced maternal age on success of TDI was illustrated in a review of cumulative pregnancy rates in women under and over 30 years of age and included data from almost 3000 cycles over a 10-year interval [51]. Women under 30 years old had higher pregnancy rates at 3, 6, and 12 months than women over 30 years old (21, 40, and 62 percent versus 17, 26, and 44 percent respectively) [51]. The maximum maternal age for administering TDI is at the discretion of the health professional or facility providing the recipient with her care.
Fresh versus frozen sperm — Cryopreservation and thaw methods decrease sperm motility and viability, which, in turn, appear to result in lower pregnancy rates. Concerns over a difference in success rates with use of fresh versus frozen donor sperm are mostly academic as current guidelines prohibit insemination of fresh donor sperm.
The lower fecundity with frozen compared with fresh sperm was illustrated in two large, randomized, crossover trials:
●In the first trial, 381 patients received alternating cycles of fresh or cryopreserved semen [52]. Fresh and frozen sperm cycles resulted in fecundity of 18.9 and 5.0 percent, respectively.
●The second trial involved 288 patients with a similar crossover design, but a higher number of motile sperm were inseminated in women in the cryopreserved arm by using a more concentrated cryoprotectant [53]. Despite this intervention, fresh sperm cycles still resulted in greater fecundity than in the group receiving cryopreserved semen (27.4 and 10.4 percent, respectively).
Recent evidence suggests that long-term cryo-storage of sperm does not impact sperm motility, which is viewed as a predictor of sperm function after thawing [54]. Also, long-term cryostorage of sperm does not impact clinical pregnancy rates with TDI [55].
Number of inseminated sperm — Data from studies in cattle show that the number of fresh sperm inseminated must be over a critical threshold to achieve maximum pregnancy rates. When declining pregnancy rates in women after insemination of cryopreserved donor sperm were noted, the possibility of a critical threshold in humans was investigated, with variable findings:
●Data from the Central Semen Bank of Denmark (n = 3418 frozen ejaculates) showed that increasing the total motile sperm count from <10x106 to 11 to 19x106 to >19x106 increased the likelihood of achieving pregnancy [56]. However, once the count was above 19x106, no additional benefit was observed.
●Another study found that frozen ejaculates with at least 20x106 sperm yielded pregnancy rates that compared favorably with fresh samples containing more sperm [57].
●By contrast, a third study found no increase in pregnancy rate when inseminating with 1x106 versus >5x106 motile sperm [58].
Although these data are discordant and there is no consensus on the optimal sperm count for insemination with cryopreserved sperm, most centers make an effort to select donors with consistently high sperm concentrations in their ejaculates. Most cryobanks seek a goal of 10 million motile sperm per vial for TDI [59]. A large number of potential donors are rejected due to inadequate sperm counts. Our minimal criteria are shown in the table (table 2).
Timing of insemination — The procedure must be done on the expected day of ovulation. Cryopreserved sperm have a shorter lifespan than fresh sperm, thus accurate timing is thought to be imperative. Insemination can be timed using basal body temperature charting, urinary LH surge, serum LH surge, and/or ultrasound findings (dominant follicle ≥18 mm) for determining ovulation. Double insemination (on two consecutive days) does not appear to increase clinical pregnancy rates [46,49].
Most centers perform a single insemination one day after the LH surge is detected in urine since the rise in urine LH occurs on the day before ovulation [60]. The rise in serum LH typically occurs approximately 36 hours before the oocyte is released from the follicle into the fallopian tube, and LH appears in the urine 12 hours after it appears in serum. (See "Evaluation of the menstrual cycle and timing of ovulation", section on 'Timing of ovulation' and "Evaluation of the menstrual cycle and timing of ovulation", section on 'Measurement of LH surge and estradiol rise'.)
Women receiving donor insemination without any infertility diagnoses can pursue TDI in natural (fresh) cycles. After 3 to 6 natural (fresh) cycles, ovulation induction with clomiphene citrate, letrozole, or gonadotropins can be considered.
Intrauterine versus intracervical insemination — Traditionally, intracervical inseminations (ICIs) were performed with fresh donor semen. A volume of 1.5 to 2.5 mL was injected into the endocervical canal; fresh specimens were not injected into the uterus due to the potential for serious reactions to proteins, prostaglandins, and bacteria. Alternative modes of insemination have been explored because of increasing concerns about transmission of sexually transmitted infections, the mandate for use of frozen specimens, and the subsequent decrease in pregnancy rates.
To date, the highest pregnancy rates have been achieved with intrauterine insemination (IUI) using washed sperm. This technique bypasses vaginal and cervical factors that might impair fertility and increases the number of sperm reaching the uterine cavity by 100-fold. A systematic review of trials comparing IUI with ICIs using donor sperm had insufficient evidence to find a difference in live birth rates between IUI and ICI in natural cycles and stimulated cycles [61]. However, IUI resulted in higher clinical pregnancy rates in natural cycles (odds ratio [OR] 6.18, 95% CI 1.91-20.03) and stimulated cycles (OR 2.83, 95% CI 1.-5.78) when compared with ICI [61]. A subsequent trial reported ICI with cryopreserved sperm to have a lower live birth rate compared with IUI with cryopreserved sperm in natural cycles [62].
OUTCOMES
Pregnancy rates — Pregnancy rates and pregnancy outcomes in fertile individuals undergoing TDI with fresh semen are comparable to those in normal controls matched for age. The success of TDI can be illustrated by the following representative examples:
●A study of couples undergoing TDI with fresh semen reported a fecundity rate (number of pregnancies/number of treatment cycles) of 20 percent and a six-cycle cumulative pregnancy rate of 74 percent, which approaches the pregnancy rate of individuals who discontinue oral contraceptive pills to attempt pregnancy [63].
●A retrospective, multicenter study compared TDI success rates in single women (n = 1402), lesbian couples (n = 585), and heterosexual couples (n = 528) compared with autologous IUI in heterosexual couples (n = 1292) over 7228 cycles [64]. Similar live birth rates were reported for all women ≤37 years of age who underwent TDI (16.5 percent for single women, 17.6 percent for lesbian couples, and 18.8 percent for heterosexual couples) compared with a lower live birth rate in heterosexual couples using autologous sperm (11 percent). Women aged 38 years or older had similar live birth rates in all groups regardless of TDI versus autologous sperm. The lower success rate in heterosexual women ≤37 years old using autologous sperm is most likely due to the higher incidence of female factor infertility in this population compared with women using TDI in the other groups.
Obstetric and perinatal outcomes
●A meta-analysis including 24 studies (no trials were identified) comparing TDI versus partner sperm found an increased risk for preeclampsia (pooled adjusted odds ratio [aOR] 1.77, 95% CI 1.26-2.48) and hypertensive disorders of pregnancy (pooled aOR 1.55, 95% CI 1.20-2.00) in pregnancies that resulted from TDI [65]. Low birth weight, preterm birth, or sex ratio were similar between groups. While risk of congenital anomalies did not appear to increase with TDI, the included studies were noted to have moderate to severe risk of bias and thus limited definitive conclusions
●A different meta-analysis of 37 studies comparing TDI versus partner sperm reported that, when compared with partner sperm, use of donor sperm was associated with an increased relative risk (RR) of combined hypertensive disorders of pregnancy (RR 1.44, 95% CI 1.17-1.78), preeclampsia (RR 1.49, 95% CI 1.05-2.09), and small for gestational age (RR 1.42, 95% CI 1.17- 1.79) [66]. The risk of ectopic pregnancy was reduced (RR 0.69, 95% CI 0.48-0.98) [66]. Similar outcomes between the two groups were reported for pregnancy loss (ie, miscarriage), gestational diabetes, pregnancy-induced hypertension, placental abruption, placenta previa, preterm birth, low birth weight, high birth weight, large for gestational age, stillbirth, neonatal death, and congenital anomaly.
Psychological outcomes — In general, studies have shown that families created via donor insemination did not differ from families with naturally conceived children with respect to the quality of parenting or the psychological development or adjustment of the child [67-72]. However, there are conflicting results regarding the effects of disclosure of origin on the parent-child relationship and psychological well-being [73]. Overall, the body of evidence does not support differences in psychological well-being of donor offspring in disclosing or nondisclosing families [73].
COST — Fees for donor sperm vary by sperm bank and are based upon how sperm were prepared (washed versus unwashed sperm) and donor characteristics (level of education). Typical prices for unwashed sperm are USD $490 to $1045, and USD $490 to $1245 for washed sperm. These prices do not include storage, shipment, routine evaluation and blood tests, or the physician fees for performing the inseminations. There are cheap online self-insemination kits; however, these are primarily intracervical inseminations, which have lower success rates than intrauterine inseminations.
LEGAL AND ETHICAL CONCERNS — Sperm donors and recipients should be informed about potential legal, medical, and emotional issues associated with donor insemination [17].
●Test results – Donors should be provided with results of their medical evaluation and laboratory tests and offered referral for further evaluation, care, and counseling, as appropriate. They should understand that they do not have control over the disposition of their sperm after it has been collected.
●Disclosures to donor and offspring – Programs vary in the information disclosed to donors about the outcome of their donation. In regions where sperm donation can remain anonymous, donors can elect to be contacted by future children when they reach age 18 years, but the social or legal ramifications are unknown.
●Legal rights and updated medical information – Social fathers are typically legally recognized as the child's father. The donor has no legal rights or duties with respect to children conceived with his sperm. However, donors and recipients have an obligation to authorize the disclosure of non-identifying medical information where appropriate. Several sperm banks offer an identity-release option, which allows banks to contact donors in the future for updated medical information and to provide identifying information to adult offspring who request it.
●Ethical use of family members as gamete donors – In the 2017 ASRM guidelines, the Ethics Committee discusses and supports the use of family members as gamete donors except when the arrangements are consanguineous or simulate incestuous relations [74]. The Committee distinguished appropriate intrafamilial reproductive arrangements from those that involved consanguinity, placed undue influence (emotional or financial) on decisions to participate, and those that raised questions about lineage and parenting relations. Additional issues that should be addressed by a qualified counselor include emotional risks, potential impact on family relationships, the donor-recipient relationship, the future role of the donor in the offspring's life, and what information will be disclosed to the offspring [75]. The ethical and legal issues of related donor insemination have been reviewed in detail elsewhere [75].
●Disclosure of donor identity – Local regulations determine whether sperm donors remain anonymous to offspring. Many argue that donors' identity should be available to allow later contact (if medically needed or desired). With the advent of genetic testing, donor-conceived children may find their half-genetic siblings in online groups. Recognition of increasing prevalence of nonmedical genetic testing that may allow previously "anonymous" donors to be identified prompted discontinuation of the term "anonymous" donor and replacement with "non-identified" [4].
•Mandated disclosure – Some countries and states have mandated that all programs use only open-identity donors [76]. While the ASRM supports disclosure of a donor's identity, forced disclosure is not regulated or required by any governing body in the United States. The number of US programs offering open-identity donors is growing, and the ratio of open-identity donors to anonymous donors tends to increase over time in programs that offer this service [77].
•Impact of mandated disclosure on donor recruitment – The impact of mandated disclosure on donor recruitment remains a point of concern. In Sweden, where legislation was passed mandating that a donor's identity be retained and made available to requesting offspring upon maturity, donor recruitment declined only transiently after the new regulations were implemented [78]. A small survey of donors in London showed that half would still donate if mandated to participate in an open-identity program; however, these were older men with children, characteristics that tend to be associated with more altruistically motivated donations [79].
•Demand for identified donors – Demand for donors willing to release their identity is unknown. Data from Canada showed that only 21 percent of 240 patients who purchased donor sperm from April 2003 through March 2005 requested sperm from donors who would agree to release their identity; however, 95 percent of women without male partners made this choice [80].
●Disclosure of TDI to offspring – Consensus is lacking as to whether or not parents should be required to disclose to their children their method of conception. In the United States, the ethics committee of the ASRM strongly encourages disclosure to donor-conceived persons, but acknowledges that recipient parents have the right to make this decision [81]. Reasons for disclosure include the child's fundamental right to know their biologic origin and avoidance of the stress that arises when secrets are kept or the information is disclosed by accident [82]. There is no good evidence that disclosure is harmful to the child.
Disclosure to donor offspring occurs earlier in lesbian couples and single mothers when compared with heterosexual couples. Even in heterosexual couples who expressed intent to disclose donor information to their offspring, fewer than 5 percent had done so by the time their child was 3 years old [83]. A longitudinal survey study of donor offspring found no overall differences in parent-child relationships or adolescent adjustment between disclosed and nondisclosed families; however, donor offspring who are told of their origins by age 7 had a better family relationship and psychological well-being in adolescence [84].
●Offspring preferences regarding disclosure – Most donor offspring want to be told about their means of conception, desire in depth information about their donor's medical and social history, and express interest in meeting their donor and extended biologic family [85]. In one study, for example, more than 80 percent of adolescents conceived with open-identity sperm donors expressed a moderate interest in requesting the identity and pursuing contact with their donor, and almost 90 percent expressed an interest in contacting others with the same sperm donor [86].
As with other ethical and legal aspects of TDI, these issues have no easy solution. However, as guidelines addressing them are developed it will be interesting to see their effect on the practice of TDI.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)
SUMMARY AND RECOMMENDATIONS
●Definition – Artificial insemination refers to the introduction of semen into the vagina, uterus, or oviduct by a means other than sexual intercourse. When the procedure is performed using sperm from a man other than the patient's partner, it is termed therapeutic donor insemination (TDI). (See 'Definitions' above.)
●Indications – Indications for donor insemination include male partner infertility, avoidance of diseases that may be transmitted or inherited from the male partner, and absence of a male partner. (See 'Indications' above.)
●Guidelines – Guidelines for the recruitment and screening of donors for the protection of both the donor and recipient are available. (See 'Guidelines' above.)
●Procedure – The procedure is performed on the expected day of ovulation using a catheter to place washed donor sperm into the uterus. Older maternal age and use of frozen sperm decrease the success rate. (See 'Procedure' above and 'Factors affecting success' above.)
●Pregnancy rates and outcomes – Pregnancy rates and pregnancy outcomes in fertile women undergoing TDI with fresh semen are comparable to those in normal controls matched for age. (See 'Outcomes' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Serene S Srouji, MD, who contributed to earlier versions of this topic review.
