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

Official title

Prospective Randomized Sibling-Oocyte Trial Comparing Fertilization and Embryo Development Outcomes Between Intracytoplasmic Sperm Injection (ICSI) and Conventional IVF Using Frozen Donor Sperm

Overview

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.

Detailed 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.

Interventions

• Procedure Intracytoplasmic Sperm Injection (ICSI)
  Mature oocytes are injected with a single frozen-thawed donor sperm cell using micromanipulation under a microscope. This fertilization method is performed shortly after oocyte retrieval. Sperm used are pre-screened and standardized for post-thaw motility and morphology. ICSI is conducted in accordance with standard embryology lab protocols. The oocyte allocation to ICSI is randomized within each participant's cycle.
• Procedure Conventional Insemination (IVF)
  Oocytes are inseminated by co-incubation with frozen-thawed donor sperm in a culture dish for 16-18 hours. Sperm are washed and prepared according to lab protocol to ensure motility and concentration suitability. This method does not involve direct sperm injection. Oocytes are randomly assigned to this method within each participant's retrieved cohort.

Primary outcome measures

• Blastulation Rate [Time frame: Day 5 to Day 7 post-insemination]

Secondary outcome measures (4)

• Fertilization Rate [Time frame: Approximately 16-18 hours post-insemination]
• Total Fertilization Failure (TFF) [Time frame: Approximately 16-18 hours post-insemination]
• Proportion of High-Quality Blastocysts [Time frame: Day 5 to Day 7 post-insemination]
• Early Clinical Pregnancy Rate [Time frame: Approximately 5 to 7 weeks after embryo transfer]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Shady Grove Fertility Rockville — Rockville

Publications

• Romero-Galisteo RP, Pinero-Pinto E, Palomo-Carrion R, Luque-Moreno C, Molina-Torres G, Gonzalez-Sanchez M. Translation, cross-cultural adaptation and validation of the Rett syndrome motor evaluation scale (RESMES): Spanish version. Eur J Paediatr Neurol. 2023 Nov;47:72-79. doi: 10.1016/j.ejpn.2023.09.008. Epub 2023 Sep 28. PMID 37788534
• Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992 Jul 4;340(8810):17-8. doi: 10.1016/0140-6736(92)92425-f. PMID 1351601
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• Teodorescu M, Barnet JH, Hagen EW, Palta M, Young TB, Peppard PE. Association between asthma and risk of developing obstructive sleep apnea. JAMA. 2015 Jan 13;313(2):156-64. doi: 10.1001/jama.2014.17822. PMID 25585327
• Mo DY, Tang YM, Wu EY, Tang V. Theoretical model of investigating determinants for a successful Electronic Assessment System (EAS) in higher education. Educ Inf Technol (Dordr). 2022;27(9):12543-12566. doi: 10.1007/s10639-022-11098-1. Epub 2022 Jun 3. PMID 35676938
• Zhang R, Xu S, Yuan M, Guo L, Xie L, Liao Y, Xu Y, Fu X. An ultrasmall PVP-Fe-Cu-Ni-S nano-agent for synergistic cancer therapy through triggering ferroptosis and autophagy. Nanoscale. 2023 Aug 3;15(30):12598-12611. doi: 10.1039/d3nr02708b. PMID 37462439

Identifiers

NCT: NCT07175571 · SISTER Study

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗