SISTER: Sibling Oocyte Insemination With Frozen Sperm From Third Party Donors: Evaluation of Reproductive Techniques

Shady Grove Fertility Reproductive Science Center

Status: Enrolling

Conditions: Fertilization in Vitro; Reproductive Techniques, Assisted; Infertility, Female

Treatments: Procedure: Conventional Insemination (IVF); Procedure: Intracytoplasmic Sperm Injection (ICSI)

Study type: Interventional

Funder types: Other

Identifiers

NCT07175571

SISTER Study

Details and patient eligibility

About

The goal of this clinical trial is to learn whether two different methods of helping eggs and sperm join-intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (IVF)-lead to better embryo development when using frozen donor sperm in people who do not have male fertility problems. The main questions it aims to answer are:

Does one method create more usable embryos (blastocysts) than the other?

Is there a difference in how often fertilization does not happen at all?

Do either of the methods lead to better embryo quality or early pregnancy?

Participants will:

Have their eggs divided into two groups. One group will be fertilized using ICSI (where a sperm is injected directly into an egg), and the other using conventional IVF (where eggs are mixed with sperm in a dish).

The fertilization method for each egg will be randomly assigned, with a random process also used to determine the assignment of any extra egg when an odd number is collected.

Continue regular fertility treatment while the study team compares the results of each fertilization method.

This study includes people with non-male factor infertility and uses frozen donor sperm. It hopes to learn whether ICSI, which is often used even when it may not be needed, truly helps improve outcomes compared to conventional IVF in these cases.

Full description

This is a prospective, randomized sibling-oocyte controlled trial designed to compare fertilization and embryo development outcomes between intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (IVF) using cryopreserved donor sperm in non-male factor infertility cycles. Despite widespread use of ICSI in assisted reproductive technology (ART), there is insufficient evidence supporting its routine use in non-male factor indications, especially in cycles utilizing frozen sperm where male factor infertility is not a contributing variable.

The study aims to address ongoing clinical debate and practice variation by evaluating whether ICSI offers meaningful advantages over conventional IVF in this specific context. Previous retrospective and meta-analytic data have suggested that while ICSI may reduce total fertilization failure (TFF), it may not improve-and may even negatively impact-other key clinical outcomes such as blastulation rate, embryo quality, and early pregnancy rates in non-male factor populations. Additionally, concerns about increased pregnancy-related complications with ICSI have been raised.

To reduce inter-patient variability and enhance internal validity, a sibling-oocyte design will be employed, allowing within-patient comparison of insemination methods. Oocytes retrieved from each participant will be randomized to either ICSI or conventional IVF. Randomization will be conducted prior to oocyte retrieval using computer-generated allocation. For patients with an even number of mature oocytes, half will be assigned to each insemination method. For those with an odd number, the extra oocyte will be randomly allocated according to the pre-specified scheme.

The fertilization process will begin shortly after oocyte retrieval. In the conventional IVF arm, mature oocytes will be inseminated using washed frozen-thawed donor sperm at a standard concentration and co-incubated for 16-18 hours. In the ICSI arm, a single motile sperm will be injected directly into each mature oocyte. All oocytes will undergo standard embryological assessment post-insemination, and embryos will be cultured under identical conditions.

The primary endpoint is the blastulation rate, defined as the number of usable blastocysts (meeting lab criteria for cryopreservation or transfer) per number of oocytes inseminated in each arm. Secondary outcomes include:

• Fertilization rate: number of 2PN zygotes per oocyte inseminated
• Incidence of TFF: no oocytes fertilized in a given arm
• Proportion of high-quality blastocysts, defined as grade BB or higher
• Early clinical pregnancy rate, as determined by ultrasound-confirmed intrauterine gestation Statistical analysis will use generalized estimating equations (GEE) for the primary outcome at the oocyte level to account for clustering within patients. Secondary outcomes will be analyzed using chi-square or Fisher's exact tests as appropriate. All data will be analyzed on an intention-to-treat basis.

The study will enroll approximately 178 participants over 12 months at Shady Grove Fertility, where frozen donor sperm with normal post-thaw parameters is routinely available. Only non-male factor infertility patients using frozen donor sperm will be eligible, ensuring a controlled sperm quality baseline across study arms.

The hypothesis is that conventional IVF will demonstrate equivalent or superior blastulation rates compared to ICSI, with non-inferior fertilization outcomes and potentially better embryo morphology. Results from this trial will help refine clinical guidelines and may support a more evidence-based, resource-efficient use of ICSI.

IRB approval has been obtained, and informed consent will be secured from all participants. All procedures will adhere to Good Clinical Practice and applicable regulatory guidelines. Data confidentiality will be maintained throughout.

Enrollment: 95 estimated patients

Sex: Female

Volunteers: No Healthy Volunteers

Inclusion criteria

• Female patients undergoing IVF with frozen donor sperm at Shady Grove Fertility Center
• Normal ovarian reserve (AMH > 1 ng/mL, AFC > 10)
• Absence of male factor infertility
• Post-wash parameters: >50% motility, >5mil concentration
• > 4 oocytes retrieved at time of transvaginal oocyte retrieval

Exclusion criteria

• Donor Sperm with significant male factor infertility (e.g., abnormal sperm concentration, motility, or morphology)
• Any medical condition contraindicating ART

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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95 participants in 2 patient groups

Intracytoplasmic Sperm Injection (ICSI)

Experimental group

Description:

In this arm, a portion of each participant's mature oocytes will be inseminated using intracytoplasmic sperm injection (ICSI). A single frozen-thawed donor sperm cell will be injected directly into each oocyte using micromanipulation techniques. The oocyte assignment to ICSI will be determined through randomized sibling-oocyte allocation. Embryos will be cultured under standard laboratory conditions and assessed for fertilization (2PN), blastulation, embryo quality, and early clinical pregnancy outcomes.

Treatment:

Procedure: Intracytoplasmic Sperm Injection (ICSI)

Conventional Insemination (IVF)

Experimental group

Description:

In this arm, a portion of each participant's oocytes will be inseminated using the conventional in vitro fertilization (IVF) method. Frozen-thawed donor sperm with normal post-thaw parameters will be co-incubated with oocytes in culture media for fertilization. The oocyte assignment to this method will be determined through randomized sibling-oocyte allocation. Embryos will be cultured under the same laboratory conditions and assessed for fertilization (2PN), blastulation, embryo quality, and early clinical pregnancy outcomes.

Treatment:

Procedure: Conventional Insemination (IVF)