Staff Quality Assurance
Staff quality assurance audits are extremely important for IVF labs! Competency and related metrics are the number one most cited IVF laboratory inspection deficiency. Embryology and andrology procedures are subjective, complex, and difficult to standardize. The lack of rigorously standardized laboratory protocols and strict quality control (QC) confounds even the best laboratories. Easily ensuring compliance with LQMS, CLIA, and WHO standards is an invaluable tool for clinics and laboratory directors. Accurate laboratory test results depend on staff being competent to perform a range of procedures and competency assessments are part of a laboratory’s quality documents, and should be periodically reviewed and used for continuous improvement.
Staff Management
You may have spent 25 years attaining the highest levels of precision and accuracy in your embryology procedures., but has anyone ever taught you how to manage staff? A rock solid team and happy balanced working environment are the keys to effective staff management and longevity of embryology teams. Teams that have played together for a long time are winning teams, teams with high embryologist turnover and burnout are constantly destabilized. In the ARTC IVF Lab Playbook, the month of October is all about preparing for the coming year. Effective staff management is a skill that IVF lab Directors can learn. Here are our suggestions!
One Month Schedule of Staff related IVF Lab QA Activities
The lab director or quality manager should each month by answering “In Progress” to each question, then assign this survey to junior staff using the “assign” function. As activities are completed or learned about, each item is marked “Complete”. This will document both continuing education and quality assurance activities.
| Competency assessments for each procedure in lab. Particularly, for clinical decisions. | Give your answers first in the ART Compass app, then assign surveys to staff: Some fun ones? Where to nick sperm tail. Where to hatch on Day 3. How to hatch blast for FET, choose to freeze or discard, to biopsy or culture more, fertilization, egg maturity, grading for day 3 / blast systems. For FETs, transfer or thaw another? |
| Eye color survey | Staff meeting to review why seeing the color red is important in an embryology lab. Assign “All About Media and pH” and “Color Vision” in ARTC. Document color vision for staff file. |
| Training documents up to date | Review training stats, 6 month review, one year review for trainees. |
| Annual procedure evaluations | Document 6 CAP checklist items for fully trained embryologists yearly. |
| Assess the IVF Lab Supervisor’s ability to supervise. | Embryology supervisors must have at least one year of supervisory experience in all aspects of embryology performed by the laboratory or a minimum of 60 cycles over a period of not less than six months. Furthermore, the performance of section directors/technical supervisors, general supervisors should be separately assessed and satisfactory. |
| Lab Director Annual Review | Lab directors can benefit from a Lean 6 Sigma approach. Gather performance reviews from someone below you, at the same level as you, and above you. What are your blind spots? Where do you excel? |
| Continuing Education Review and plan for upcoming year | There must be a functional continuing laboratory education program adequate to meet the needs of all personnel. The ARTC IVF Lab playbook provides suggestions for CE activities for each month, and methods for easy documentation and automated follow up. Additionally, discuss with staff research interests, desire to attend conferences and dates, and plan the advanced off-site plan for continuing education. |
| Staff degree or certificate posted | Certificates can be posted above computer work stations. |
| Update personnel records. | Upload job descriptions, CV, resume, transcripts for foreign degrees, and continuing education certificates to your ARTC profile. |
| Update Organization Chart | There must be an organizational chart for the laboratory, or a narrative description that describes the reporting relationships among the laboratory’s owner or management, the laboratory director, section director(s)/technical supervisor(s), technical consultant(s), clinical consultant(s), and supervisor(s)/general supervisor(s), as appropriate. |
| Order Holiday or World Embryologist Day Gifts | Great gifts for embryologists can be found here, here and here! |
| Plan Holiday Party | Where will your team celebrate the years achievements and accomplishments, and bond together outside of work? A restaurant, bar, or park? |
CLIA regulations require laboratories to participate in some form of proficiency testing (PT) for every test that they perform on patient specimens at an interval of not less than twice per year. Accrediting agencies may have their own PT requirements for non-diagnostic tests or services such as those provided by the Embryology laboratory. Examples of testing that requires a minimum of an alternative assessment (not external PT) include sperm morphology, sperm motility, sperm choice for ICSI, where to nick a sperm tail and all embryology procedures/tests; oocyte maturity, fertilization check, day 3 grading, day 3 hatching, blastocyst grading, decision to freeze, decision to biopsy, decision to transfer or thaw another among others.
ART Compass provides HIPAA-compliant ways to assess the clinical decision making of ART laboratory staff for andrology and embryology competency. The competency assessment modules provide standardized instructions to test-takers and can be used to measure inter and intra- technologist variability between embryologists. Competency assessment surveys have been designed to allow the ART/ IVF laboratory director to gain insight into the clinical decision making of the most senior staff and compare that to junior staff members. For example, for choice of sperm for ICSI, or top choice of embryo for cryopreservation, biopsy, and transfer, and inform the key performance indicators (KPIs) used to continuously monitor and assess culture conditions. Mobile application technology was designed to allow standardized specimens to be served to each technologist at each study site simultaneously, allowing even very small IVF clinics to compare an individual technician’s values to the mean of all technicians and to technicians in a central laboratory. Test pictures, videos, and written test questions are randomly refreshed from a large database of multimedia files to eliminate bias.
Current assessments methodologies are extremely limited, perhaps to just one cleavage stage embryo and one blastocyst image every 6 months, and they cannot be customized to a lab’s own grading system or clinical question(s) of interest to that particular lab. ART Compass assessments are unlimited and completely customizable- from the images to the buttons to the test directions and the pre-test video can deliver learning content or instructions and demonstrations. They have also been validated and you can read more in JARG and Human Reproduction.
ART Compass Features
The mobile app documents ALL aspects of laboratory information assessment, not just for embryos and sperm but including; basic lab, continuing education, biohazard safety, handwashing, color vision, and FDA regulations among many others. ART Compass provides standard forms used by all employees. It documents competency assessment records, time and date stamps results, and is completely confidential. These records become part of the laboratory’s quality documents, and can be periodically reviewed and used for continuous improvement and quality assurance.
| WHO Competency Assessment Procedure Recommendations | ART Compass Features |
| The assessor contacts the employee in advance to inform her/ him that the assessment will be done at a prearranged time. | Push notifications, employee dashboard, application inbox. |
| The assessment can be done while the employee is performing tasks using routine sample images. | Smart-phone design allows for integration into daily work flow. Multimedia image and video databases eliminate bias and are more similar to routine sample analysis. |
| The assessment is done by a specified method previously described and is recorded in a digital “logbook.” | Standardized test protocols and check for understanding modules. A digital record is permanently saved to the administrator console and displayed in director and technologist dashboards. |
| The results of the assessment are shared with the employee. | Technologist dashboard |
| A remedial action plan is developed defining required retraining. | The app communicates specific steps to be taken to correct the problem with related deadlines, date and time stamped, through the inbox. For example, the employee may need an updated version of the standard operating protocol (SOP). |
| The employee is asked to acknowledge the assessment, related action plan, and reassessment. | Inbox records the interaction and response and date and time stamps it. Tests attempted, completed and passed, or tests to be re-attempted are prominently displayed through badges on the technologist dashboard. |
Additionally, pictures, videos, and written test questions are randomly refreshed every month from a large database of multimedia files to eliminate bias (being familiar with images and expected answers for example) for an ART laboratory’s quality assurance plan.
Evaluating and documenting competency of personnel responsible for testing is required at least semiannually during the first year the individual tests patient specimens, and at least annually thereafter. Competency assessment must be performed for testing personnel for each test that the individual is approved by the laboratory director to perform. The following six (6) procedures are the minimal CLIA regulatory requirements for assessment of competency for all personnel performing laboratory testing.
| CLIA Requirements | ART Compass Annual Procedure Evaluation |
| Direct observations of routine patient test performance, including patient preparation, if applicable, specimen handling, processing and testing. | Observation of Performance |
| Monitoring the recording and reporting of test results | Test Report Completion |
| Review of intermediate test results or worksheets, quality control records, proficiency testing results, and preventive maintenance records | QC/PT/PM Records |
| Direct observations of performance of instrument maintenance and function checks | Instrument Maintenance |
| Assessment of test performance through testing previously analyzed specimens, internal blind testing samples or external proficiency testing samples | Peer Assessment |
| Assessment of problem solving skills | Problem Solving |
September is a great time to perform an FDA Compliance quality assurance audit in your IVF Lab! Visit the IVF Lab Playbook.
| September | FDA Audit |
| October | Staff Audit |
| November | Patient Satisfaction and Security |
| December | Space and Supplies |
| January | Preventative Maintenance, Air Quality, and Deep Clean |
| February | Biennial P&P Updates, Review, and Sign Off |
| March | General IVF lab CAP Inspection Preparations |
| April | |
| May | |
| June | |
| July | |
| August |
September is a great time to perform an FDA Compliance quality assurance audit in your IVF Lab!
This blog post will provide you with a month’s schedule of specific quality assurance activities that will keep your IVF lab compliant with FDA Title 21 Code of Federal Regulations (CFR) Part 1271 and College of American Pathologist inspections. It will also provide background on FDA and CAP requirements.
FDA requires prospective egg and sperm donors to be tested for HIV, Hepatitis B and C, chlamydia, and gonorrhea, and for stored embryos, eggs, and sperm to be labeled so they don’t get mixed up. The FDA has the power to inspect and shut down IVF labs if they don’t meet the legal requirements.
Donated reproductive tissue (eggs or sperm) are regulated as human cells, tissues, and cellular and tissue-based products (HCT/Ps). Any establishment that performs one or more manufacturing steps for HCT/Ps (recovery, processing, storage, labeling, packaging or distribution of products) must register with FDA and list their HCT/Ps in accordance with Title 21 Code of Federal Regulations (CFR) Part 1271.
Reproductive HCT/P donors are required to be screened for risk factors that may increase the chances of transmitting a communicable disease.
Donor screening consists of reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases. These records include a current donor medical history interview to determine medical history and relevant social behavior, a current physical examination, and treatments related to medical conditions that may suggest the donor is at increased risk for a relevant communicable disease.
FDA Donor HCT/P Eligibility Determination: 3 Necessary Factors
Donor screening must document three items: donor medical history (ie risk factor assessment), physical exam and review of other relevant medical records, and donor infectious disease testing. After those items are reviewed by a physician or responsible person, a donor eligibility determination can be made. Donors can be deemed “eligible” for anonymous donation, or “ineligible” (and therefore the donation can only be directed, not anonymous). An ineligible directed reproductive tissue donor can provide semen, oocytes, or embryos, to a specific recipient, and who knows and is known by the recipient before donation, provided they are counseled appropriately and sign a waiver.
What is the IVF lab’s responsibility for maintaining FDA compliance?
Both FDA and CAP have specific requirements for IVF labs to follow. The IVF laboratory must be registered with FDA and have a procedure for reporting device-related adverse patient events, donor records must include a statement of eligibility or ineligibility and a summary of the records used to make the donor-eligibility determination, and there must be a written procedure for investigating donor infections or adverse events after reproductive donor cells/tissues are received or implanted.
Donor cells/tissues must be labeled with the following information in accordance with the intended use:
- Unique identification code
- Description of the type of cells/tissue(s)
- Expiration date (if any)
- Warnings (if any)
- Name and address of the establishment that made the eligibility determination and made the cells/tissue(s) available for distribution
Furthermore, for testing performed by clinical lab staff in Endocrinology or Andrology, prior to clinical use of each modified FDA-cleared or approved test and laboratory-developed tests (LDTs), the laboratory must perform a validation study and prepare a written assessment of each of the following test method performance specifications. Whenever available, reagents and supplies used in the collection, processing and cryopreservation of gametes and/or embryos should be cleared or approved by FDA for human use.
Lastly, the entire staff should be competent in FDA related skills and knowledge, and the IVF laboratory director or designee must interact with agencies FDA, as appropriate, for laboratory-related matters.
| FDA Related CAP Requirements | |
| GEN.20351: Adverse Patient Event Reporting | |
| RLM.12455: FDA Registration | |
| RLM.12510: Donor Cells/Tissues Labeling | |
| RLM.12587: Donor Infection/Adverse Events Investigation | |
| DRA.11450: Director Responsibility – Interaction with Government or Regulatory Interaction | |
| COM.40350: Validation of Test Performance Specifications | |
| RLM.03480: FDA-Cleared/Approved Reagents and Supplies |
One Month Schedule of FDA related IVF Lab QA Activities
Start each month by answering “In Progress” to each question, then assign this survey to junior staff using the “assign” button. This will document both continuing education and quality assurance activities.
| Create or update a schematic map of all tank or canister eligibilities | Post up to date schematic in tank room(s). Download our editable template here! Tank-Schematic-1-1. |
| Review Tissue in Donor Canisters/ Tanks | Move all eligible donors to a single canister or tank. Update cryo records and log books. |
| Separate Sperm and Egg Bank Donor Binders | Particularly review shipping records to ensure that when donor tissue is received it is located in the correct binder, tank, and canister. |
| Take the FDA Survey in the ART Compass app and assign survey to staff | Review competency results and assign any needed remediation. Download the free ART Compass app Apple App Store: https://itunes.apple.com/us/app/art-compass/id1442048939?mt=8 Google Play Store: https://play.google.com/store/apps/details?id=com.artproficiencyapp |
| Update FDA Cryopreserved tissues eligibility forms | Copy language directly from HCTP and replace out of date language. |
| Review Summary of Records forms | Update out of date language by reviewing FDA Warning Letters (search for “fertility”). |
| Review Donor Risk Checklist / Questionnaire for updated risk questions | Update out-of-date language by reviewing FDA Warning Letters (search for “fertility”). |
| Review Requisitions for tissue type – anonymous, directed donor, and for future GC | Correct sperm freezing, egg cryo, and IVF requisitions so that IVF Lab can put an accurate FDA Cover sheet or sticker with each cryo record. |
| Review FDA eligibility form or stickers with each cryopreserved tissue by randomly selecting 10 GC transfers, 10 Egg Donor Embryos, and 10 Sperm Donor Embryos | Hold a staff meeting to ensure that each FDA eligibility status’ are used correctly. Goal of 100% compliance. Document staff/ lab meeting. |
| Review one full binder of sperm records and one full binder of embryo records for presence of FDA Eligibility sheets or stickers. If missing more than 3 per binder review all binders. | Replace or correct any FDA Eligibility sheets in each binder. |
| Read and sign off on all FDA related policies and procedures | Document each person for each Policy and Procedure. Assign them to staff and records annual sign offs in the ARTC Document control system. |
| Read FDA Warning Letters for fertility clinics. | Discussion deviations in a lab meeting and document meeting. |
| Review all tests and devices used and check for new FDA approved products. | Still using unapproved tests or devices? Are there any new tests of devices that can replace the unapproved ones? |
| Review any FDA reportable adverse donor or device events | Perform a Root Cause Analysis to determine the cause of any incidents. Notify the Laboratory Administrator and the Laboratory Director of the findings. Complete FORM FDA 3500 either in paper format or online at www.fda.gov/medwatch/report.htm |
| IVF Lab Director Responsibilities | Create a folder with evidence of compliance, such as records, reports, or responses to FDA. Make sure to notify FDA of any change in directorship! Update FDA Registration menu. |
| Audit companies that perform any manufacturing step for the IVF laboratory | Check the FDA website for current registration, possible FDA actions against contractors, and patient comments. Take action on any notification of defects or issue with supplies that may affect patient care and document actions. |
| Hold Mock FDA Inspection. | Are you ready for FDA to show up at your IVF Clinic? Review electronic medical records of donor tissue recipients and “provide recommendations” in a mock inspection. |
| September | FDA Audit |
| October | Staff Audit |
| November | Patient Satisfaction and Security |
| December | Space and Supplies |
| January | Preventative Maintenance, Air Quality, and Deep Clean |
| February | Biennial P&P Updates, Review, and Sign Off |
| March | General IVF lab CAP Inspection Preparations |
| April | |
| May | |
| June | |
| July | |
| August | |
There are so many exciting talks at ASRM2021, Reproduction Reimagined! We are super excited about these IVF Lab focused talks as well as quite a few others!
| Title | Speakers |
| O-199 – COULD THE EMA ARTIFICIAL NEURAL NETWORK GRADE BLASTOCYSTS AS AN EMBRYOLOGIST? | Lorena Bori, Ph.D1., Daniella Gilboa, MSc2, Ron Maor, BSc.2, Thamara Viloria, PhD3, Ilya Kottel, BSc.2, Daniel S Seidman, MD4 and Marcos Meseguer, Ph.D.1, (1)IVIRMA Global; IVI Foundation, Valencia, Spain, (2)AiVF, Tel Aviv, Israel, (3)IVIRMA Global, Valencia, Spain, (4)AiVF; Sackler Faculty of Medicine, Israel |
| RTM32 Ready, Set, Go! How to Skyrocket Your ART Lab Professional Career. | Liesl Nel-Themaat, Ph.D., HCLD, University of Colorado Anschutz Medical Campus, Aurora, CO |
| RTT27 Emerging Bioengineering Technologies in the ART Labs | T. Arthur Chang, PhD, HCLD, ELD, University of Texas Health Science Center, San Antonio, TX |
| RTT28 “Be a Scientist, Not a Robot”. Is That a Lost ART?” | Mitchel C. Schiewe, MS, PhD, Ovation Fertility, Newport Beach, CA |
| RTT29 The Ideal Cryopreservation Storage System – Characteristics and Equipment. | Kimball O. Pomeroy, Ph.D., The World Egg Bank, Phoenix, AZ |
| INT03 To ICSI ALL or NOT to ICSI ALL: That’s the Question! | Mitchel C. Schiewe, MS, PhD, Ovation Fertility, Newport Beach, CA, David H McCulloh, PhD, NYU Grossman School of Medicine, New York, NY, Caroline McCaffrey, PhD, NYU Langone School of Medicine, New York, NY, Bill Venier, MSc, ELD (ABB), San Diego Fertility Center, San Diego, CA and Liesl Nel-Themaat, Ph.D., HCLD, Univ of Colorado |
| RTW21 Looking Past the Hype: Realistic Expectations for AI-Based Embryo Selection. | Dean E Morbeck, Ph.D., M.B.A., Fertility Associates, Auckland, New Zealand |
| RTW22 Lab Disaster Management: Prepare Today be Ready Tomorrow | Sangita K Jindal, Ph.D., Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY |
| RTW23 New Lab Equipment: Better Outcomes? | Anthony R Anderson, D.HSc, EmbryoDirector.com, San Antonio, TX |
| SYW06 Crises Management: What We Have Learned from Catastrophic Events | Roman Pyrzak, Ph.D., Kimball O. Pomeroy, Ph.D., The World Egg Bank, Phoenix, AZ and Sangita K Jindal, Ph.D., Albert Einstein College of Medicine / Montefiore Medical Center, Hartsdale, NY |
| SYW07 ON-DEMAND ONLY SESSION: The Environment: It Affects More Than the Ice Caps! | Patricia Hunt, Ph.D.1, Dean E Morbeck, Ph.D., M.B.A.2 and Linda C Giudice, MD, PhD1, (1)Washington State University(2)Fertility Associates, Auckland, New Zealand |
| PLE05 Herbert H. Thomas Plenary Lecture: Applications of Nuclear Transplantation in Reproductive Medicine | Shoukhrat Mitalipov, PhD, Oregon Health & Science University, Portland, OR |
| PLE06 Past and Future of IVF | Eli Y Adashi, MD, The Warren Alpert Medical School, Brown University, Providence, RI |
| INM08 Snap, Tweet, Tok! Reimagining Patient Education with the Use of Social Media | Natalie M Crawford, MD, MSCR, Fora Fertility, Austin, TX, Jasmine Danielle Johnson, MD, IU Health – Indiana University School of Medicine, Carmel, IN and Temeka Zore, MD, Spring Fertility, San Francisco, CA |
| SYT07 Artificial Intelligence (AI) in the IVF Laboratory | Alan B Copperman, MD, Sema4, Stamford, CT, Richard Slifkin, BA, TS(ABB), CLT(NYS), Reproductive Medicine Associates of New York, New York, NY and Danielle Soltesz, MBA, MPH, RMA of New York, New York, NY |
| YM04 PGT Yesterday, Today, and Tomorrow | James A Grifo, MD, PhD, New York University, New York, NY, Mike Large, Ph.D., CooperSurgical, Houston, TX and Mark Hughes, Ph.D., COOPERGENOMICS |
| RTM22 What the IVF Doctor Needs to Know about the IVF Laboratory | Eric J. Forman, M.D., Columbia University Fertility Center, New York, NY |
| RTM08 Polygenic Risk Scores and Embryo Selection: Should We? | Amber Gamma, MS, CGC, Northwell Health Division of Medical Genetics, Great Neck, NY |
| SYM10 SART-CORS Registry: The State of the ART | Jennifer F Kawwass, MD, Emory University School of Medicine, Division of Reproductive Endocrinology and Infertility, Atlanta, GA, Stacey A Missmer, Sc.D., College of Human Medicine, Michigan State University, Grand Rapids, MI and Amanda Nicole Kallen, MD, Yale School of Medicine, New Haven, CT |
| INT02 Chat with Journal Editors: Good Scientific Publication, Manuscript Review, and Editorial Process | Alexander M. Quaas, MD, PhD, University of California San Diego, San Diego, CA, Richard J Paulson, MD, MS, University of Southern California, Los Angeles, CA, Denny Sakkas, PhD, Boston IVF, Waltham, MA and David F Albertini, PhD, M.S., Bedford Research Foundation, Salisbury, MA |
The importance of the embryologist’s role in embryo freezing, also called cryopreservation, has grown with the rise in pre-implantation genetic testing and “freeze-all” strategies. Embryo cryopreservation and maintenance is considered to be a standalone sub-discipline of reproductive medicine. Embryo cryopreservation allows women undergoing IVF to have just ONE cycle, but continue to have embryos to use in the future. It helps to reduce the risk of Ovarian Hyperstimulation Syndrome (OHS), and allows for the endometrium to fully recover after ovarian stimulation.
History of Cryopreservation
The idea of maintaining the viability of living reproductive cells and tissues of various species and humans for long-term storage has been around for almost 50 years. Dr. Alan Trounson and Linda Mohr achieved the first human pregnancy from a frozen (8 cell) embryo in 1983 and the first live birth, baby Zoe, in 1984. In 2017, Emma Wren Gibson was born from an embryo that had been frozen for nearly 25 years – possibly the longest gap between conception and birth since IVF began.
Overall, embryo cryopreservation has decreased the number of fresh embryo transfers performed, and maximized the effectiveness of IVF cycles.
- Data shows that women who had fresh and frozen embryo transfers obtained an 8% increase in additional births using cryopreserved embryos.
- Randomized clinical trails (Coates 2017 and Magdi 2017) show that vitrification of blastocysts and frozen embryo transfer (FET) is superior.
Vitrification for embryo freezing
Through efforts to constantly improve cryopreservation techniques, we are now able to preserve cells and tissues through a process called vitrification – transforming cells from a liquid state directly to a glass like state. This is done by replacing all the water in cells (dehydration) with a cryopreservation agent, and then by cooling the embryos to extremely low temperatures, such as −195.79°C (the boiling point of the liquid nitrogen). Cooling down biological objects to such degrees prevents any biological activity, including all the biochemical reactions involved in cell death!
Roles & Responsibilities of Embryologists
When cryopreservation methods fail, dreams and families are lost. Several high profile cases of liquid nitrogen storage failures, as well as the selection and transfer of the “wrong” embryo have been nightmare scenarios for the IVF industry. They highlight the embryologist’s important role in cryopreserving and storing embryos. Some of the roles and responsibilities of embryologists are:
- To label, separate, and store embryos that are potentially infectious (for example, created with HIV+, Hepatitis + eggs or sperm) for use by a sexually intimate couple, for use by an unrelated gestational surrogate, or in cases of embryo adoption.
- To understand embryo inheritance in cases of death, or use by either party in cases of separation and divorce.
- To discard embryos that are genetically abnormal, or after individuals have completed building their families.
- To collect and organize legal consents to store frozen embryos, to thaw embryos for transfer (or biopsy), or discard the tissues.
- To correctly label, identify, and select embryos for transfer.
- Maintain liquid nitrogen dewars at all times – over holidays and weekends- with optimal and adequate levels of freezing cold liquid nitrogen.
- Detect environmental changes, inspect the condition of storage vessels, and, maintain alarm systems and liquid nitrogen gas supplies.
- Ship (and receive) frozen embryos (and eggs and sperm) all around the world!
Sperm Preparation for ART is necessary! When sperm is ejaculated it is surrounded by fluid (seminal fluid). A typical ejaculate contains cells, debris, dead and damaged sperm, and healthy, motile sperm. Healthy sperm is critical to the success of ART procedures and so we use sperm preparation techniques to separate functional spermatozoa for IUI, IVF, and ART and for cryopreservation. In the IVF lab there are essentially 4 techniques we use commonly; Swim-up, Swim-down, Sucrose and Ficoll-400 density gradient techniques. Each lab finds that one of these techniques will yield more motile, live and normal looking sperm for their procedures.
The density gradient sperm wash is one of the most popular sperm washing methods. This is because it also works to separate dead sperm cells, white blood cells, and other waste products from the sperm. A test tube is filled with multiple layers of liquids of different densities. Semen is then placed on the top layer of liquid and the test tube is spun in a centrifuge. After it is spun, active, healthy sperm will make their way, to the very bottom layer of the liquid in the test tube, while debris and dead sperm will get caught in the top two layers. These layers can be siphoned off, in order to remove the active sperm from the test tube.
Companies like ZyMot sell specialty devices for sperm preparation and separation that can be very expensive. The idea is that they simulate the cervical and uterine pathways that sperm must navigate to naturally fertilize an egg. By mimicking this natural selection method, sperm can be isolated without the use of chemicals or centrifugation that may damage the sperm. Instead they use microfluidic technology to isolate healthy sperm by laminar flow, which creates gradients through channels. These devices have been tested in randomized controlled trials, which is the gold standard of medical research.
ICSI was developed for men with poor sperm quality and quantity. Low sperm count, sperm motility, and abnormal morphology can be indications for ICSI. Abnormal morphology (shape of sperm) has been linked to poor fertilization. Fertilization can now be achieved for men where it previously seemed impossible. It is now used exclusively in some clinics, and it is especially important for couples who want to have their embryos genetically tested. One of the reasons why it is so widely used now, is so that the embryologists can look at the eggs and know the quality and maturation right after the egg retrieval. In conventional IVF, the egg quality and maturity is essentially a mystery because the eggs are surrounded by cells until the day after the fertilization. Fertilization rates are generally higher after ICSI compared to conventional IVF. The more embryos you have the better the chance of pregnancy!
One variation of ICSI is called “PICSI” which stands for physiological ICSI, and uses a specialized dish coated in a substance called hyaluronan. Healthy sperm are attracted to that enzyme and stick to it, they are later used to inject the egg with.
Collecting Sperm Samples At Home
Some IVF labs may request that you and your partner collect the semen sample at home. Should patients be worried about the quality of the sample?
Originally, IVF labs insisted on “on site” collection, due to chain of custody and identification requirements. We want to see your husband/ partner face, match it to their ID, and know that the sample left their body and went straight into our own hands.
Should you be worried? It depends on the starting quality of the sperm. 99.9% of samples will be absolutely fine. In fact, once the sample makes it into the lab, it’s going to sit and “liquify” anywhere between 20 minutes to an hour or more. If male factor infertility is present, then it’s probably best to be collected in lab. For example, if retrograde ejaculation is suspected, then we need to collect all the urine AFTER the ejaculation event. Sperm are extremely hardy, and in fact they prefer a bit lower temperatures. Room temperature is perfect. Sperm are designed to withstand days in the punishing and selective vagina, cervix, and reproductive tract. The vagina first tries to kill all the sperm with acidic secretions and white blood cells. Then it sets the sperm on a race through a maze (cervix-uterus-fallopian tube), to reach the egg. In the collection cup, the sperm will be protected in the seminal fluid, and nurtured by the sugars present in it. Just follow all the lab instructions, don’t let the cup get too hot or too cold. Deliver it during the right window of time.
Sperm Preparation Techniques for HIV+ Patients
Data shows that up to 25% of semen specimens from men with an undetectable burden of viral RNA (HIV particles in their blood) are HIV positive. Each semen sample must be tested because those results are not consistent. HIV is detected in some samples and not others from the same man, even when HIV is not detected in the blood. SPAR stands for special program of assisted reproduction. They have developed highly sensitive techniques for sperm preparation, to detect the viral load in semen samples viruses like HIV, CMV, and Hepatitis C, and special procedures to wash the semen samples. This allows the sperm to be used for IVF to decrease or virtually eliminate the risk of transmitting the infection. These specimens can only be used for IVF, they are not appropriate for intrauterine insemination.
Male Fertility and Lifestyle Factors are present in up to half of couples. The prevalence of male infertility makes semen analysis one of the most important fertility tests, and it should be performed prior to any female therapy.
Male infertility means that a man may not deliver the appropriate quantity or quality of sperm to reach and fertilize an egg. Sperm are manufactured in the testicles and travels through the epididymis and the vas deferens when ejaculated. Sperm require three months to develop, which means a semen analysis done today is reflective of the conditions three months earlier. The conditions that originally caused male infertility may no longer be present. The IVF Lab will gently wash and prepare the sperm for your ART procedure. Each lab has a slightly different method to separate the sperm with the highest motility for use in IVF or ICSI.
It seems obvious that heavy alcohol drinking can impair sperm production and disrupt hormones in men while in women it can increase the time it takes to conceive. Smoking can damage sperm DNA in men or damage eggs and affect ovulation in women. Fertility specialists often recommend not consuming caffeine and alcohol during fertility treatments. The study “Alcohol and Caffeine Consumption and Decreased Fertility,” published in Fertility and Sterility demonstrates just that. But did you know about these 5 things that can negatively impact male fertility?
1. Did you know drinking soda has been linked with a 20% reduction in the average monthly probability of conception for both men and women? Energy drinks likely have the same effect but require more study (Boston University, Hatch et al.)
2.The following common medications may cause male fertility problems: some antibiotics, spironolactone, cimetidine, nifedipine, sulfasalazine and colchicine.
3. Very common STIs such as chlamydia, gonorrhea, mumps or HIV and other health conditions, such as diabetes, high blood pressure and depression
4. Enlarged veins in the tested (varicocele).
5. Constant exposure to high temperatures, like saunas or hot tubs, laptop computers, or workers exposed to heat stress.
Male Infertility Diagnoses
Sperm Motility
Sperm motility is important in fertility because sperm need to move through the woman’s reproductive tract to reach and fertilize her egg. Poor sperm motility can be a cause of Male Factor Infertility.
Did you know that infertility due to male factors ranges from 20% to 70% and that the percentage of infertile men ranges from 2·5% to 12% worldwide? Infertility rates are highest in Africa and Central/Eastern Europe. Additionally, according to a variety of sources, rates of male infertility in North America, Australia, and Central and Eastern Europe vary from 4 5-6%, 9%, and 8-12%, respectively.
The causes of low sperm motility vary, and many cases are unexplained.
Damage to the testicles, which make and store sperm, can impact the quality of sperm.
Common causes of testicle damage include:
infection
testicular cancer
testicular surgery
an issue a man is born with
undescended testicles
injury
The long-term use of anabolic steroids can reduce sperm count and motility. Drugs, such as cannabis and cocaine, as well as some herbal remedies, can also affect semen quality.
A varicocele is a swelling of the veins that drain the testicle, which can impact sperm quality. Varicocele has also been associated with low sperm motility.
Sperm DNA Fragmentation
DNA fragmentation can be caused by a variety of factors such as infection, chemotherapy, radiotherapy, smoking, drug use, or advanced age. SDF is linked to impaired fertilization, poor embryo quality, increased spontaneous abortion rates and reduced pregnancy rates after assisted reproduction.
Sexually transmitted infections
STDs can also cause infertility in men. The process can be similar to how PID damages a woman’s fallopian tubes. The structures of the male reproductive tract, including the epididymis and urethra, can be damaged by infection with an untreated STDs. Chlamydia and gonorrhea are the first and second most commonly reported notifiable disease in the United States.
Sexually transmitted infections (STIs) are common. People who have a STI often have no symptoms.
Extremely common STIs like chlamydia, gonorrhea, syphilis, and mycoplasma genitalium can damage the reproductive organs and cause infertility.
Sperm Agglutination
Sperm agglutination refers to the percentage of sperm that stick together. Male infertility is sometimes caused by the male developing antibodies to his own sperm, which increases agglutination in the semen. This usually results after a trauma to the testicles or surgical procedures such as a vasectomy reversal. When present, anti-sperm antibodies can bind to the sperm, essentially interfering with fertilization and motility.
Ejaculation disorders include premature ejaculation, anejaculation (the failure to ejaculate), and retrograde ejaculation, which is when semen enters the bladder during orgasm instead of coming out the tip of the penis.
Prior vasectomy, inguinal hernia repairs, scrotal or testicular surgeries, prostate surgeries, and large abdominal surgeries performed for testicular and rectal cancers risk, among others.
A suggestion originated in the early 2000s that the high hormone levels derived from a stimulated IVF cycle would encourage a non-receptive, out-of-phase endometrium, the concept arose that adopting a freeze-all approach would not only minimize the risk of ovarian hyper response syndrome but maybe even improve pregnancy rates in the general IVF population. The Freeze all Embryos or Fresh Transfer strategy was initially a ‘rescue’ strategy for women at high risk of ovarian hyperstimulation syndrome; however, this approach has been extended to other indications as a scheduled strategy to improve implantation rates.
The latest clinical meta-analysis of fresh vs frozen transfers, now involving 5379 eligible subjects and 11 trials, found eFET associated with a higher live birth rate only in hyper-responders. There was no outcome difference between fresh and frozen in normal responders, nor in the cumulative live birth rate of the two overall groups. Now, here is where it gets complicated.
The CDC described the increase in the number of elective FET cycles between 2007 and 2016 as ‘dramatic’, rising steeply from almost zero to more than 60,000 cycles per year. In its summary of US activity for 2016 the CDC seems unequivocal – at least, based on its observational registry data – that rates of pregnancy and live birth are higher after frozen transfers than after fresh. Yet the (published, peer-reviewed, or randomized clinical trial) so far has not shown a large difference. It seems to be a case where the clinical trials have not caught up with clinical practice, and because there is clear evidence that for hyper responders outcomes are better, many clinics are now relying on a Freeze all Embryos or Fresh Transfer strategy to reduce this poor outcome.
Are you a good candidate for “Freeze all”?
Mathilde Bourdon et al., (RBMO, 2021) recently summarized the evidence in The freeze-all strategy after IVF: which indications?
The use of this strategy is steadily increasing in ART cycles with various indications
1. To counter the risk of late pregnancy- induced ovarian hyperstimulation syndrome (OHSS) in patients who experienced an excessive ovarian response to stimulation
2. The existence of endometrial anomalies, e.g. thin endometrium, polyps, associated metrorrhagia, submucosal leiomyomas and endometritis, or elevated progesterone levels on the last day of stimulation.
3. The aim was to limit the risk of implantation failure or was used as a ‘scheduled’ strategy before the beginning of ovarian stimulation in various indications, including preimplantation genetic testing (PGT).
4. Ovarian stimulation with IVF and intracytoplasmic sperm injection (ICSI) cycles could have a negative effect on endometrial receptivity, generalization of the freeze-all strategy to the overall IVF/ICSI population has since been implemented in a number of centers.
5. A recent meta-analysis, the transfer of day-5 blastocysts was associated with significantly higher pregnancy rates compared with the transfer of day-6 blastocysts as the intrinsic embryo implantation potential in day-6 blastocysts is impaired (Bourdon et al., 2020a), an asynchrony between the endometrium and day-6 blastocysts is also a possibility, reported significantly lower live birth rates in fresh day-6 compared with fresh day5 blastocyst transfers, whereas this difference was not found with frozen embryo transfer
6. It may also be caused by a failed implantation process, possibly related to the endometrial changes that impair endometrial receptivity in fresh autologous IVF/ICSI cycles
7. Freeze-all strategy increase the chances of a live birth in women with repeated IVF/ ICSI failures, women with at least one failed fresh blastocyst transfer have a significantly greater probability of a live birth with the ‘freeze-all’ and subsequent thawed approach than with another fresh cycle
8. IVF is associated with an increased risk of thromboembolic diseases (pulmonary embolism and venous thrombosis), with a doubling of risks during pregnancies resulting from ART.
Have you ever wondered how The Development of IVF came to be? When certain discoveries took place? In this post, we’ve included some of the milestones that were reached during the process of developing IVF! It’s important to appreciate the hard work of countless scientists across the field who made this happen.
Image by Sarah Pflug
The Development of IVF, Can you believe there was a time prior to the 1800s when we did not know what cells were involved in reproduction? We did not know that a sperm and an egg are required to fuse, forming a zygote that will continue to divide until it becomes an embryo, a fetus, and then a full-grown baby. After the discovery of microscopic sperm and eggs, our whole view of reproductive health changed. We started to explore the causes of miscarriages and infertility, and a multitude of scientific endeavors manipulating eggs, sperm and embryos in the lab followed.
One of the first assisted reproductive acts that were performed in the 1800s was artificial insemination. It ended in a miscarriage, but another attempt at insemination quickly followed, but this time donor sperm was used. Something to note here is that the couple opting for the insemination was not notified of the use of donor sperm. Such a lack of transparency is unthinkable in today’s infertility medicine.
Then came some girl power! In the 1900s Miriam Menkin, a scientist in Dr. Rock’s lab made a serendipitous discovery that ultimately led to the success of Development IVF. She had finally stumbled across the fusion of a sperm and egg outside the human body, a discovery would have been undoubtedly delayed without her. By 1978 the world finally had its first-ever successful IVF pregnancy. The 1980s had more scientific endeavors in store for the world as well. Ovarian stimulation was a significant discovery.
Being able to control the ovaries to produce eggs just at the right time for collection, was a game-changer. There was a shift from using human chorionic gonadotropin (hCG) to using gonadotropin-releasing hormone and GnRH antagonists which allowed for more control over stimulating oocytes. This, however, also led to the discovery of ovarian hyperstimulation syndrome, which is a side effect of excessive stimulation of the ovaries that can lead to renal failure and possibly even death. This may potentially be the result of the follicles as once they are in the body, they could produce high levels of estradiol. After this realization, physicians now monitor follicles after they have been stimulated and patients are continually checked to know if they are at high risk for developing OHSS.
Infertility clinics, one of the pivotal aspects of fertility care, were also created in the 1900s. It’s crazy to imagine a time where if a couple was struggling with infertility, there was not necessarily a place to go for help. Another crucial piece of the puzzle was our understanding of the importance of embryo culture. Ensuring that your embabies are growing in a healthy and safe environment matters! That is why developing the perfect medium for them to grow in is essential for their wellbeing. Sugars, growth factors, and amino acids are examples of what are found in this medium that supports the embryo during it’s critical initial developmental stages.
Today’s reproductive health looks a lot different from decades ago. Today we have preimplantation genetic testing (PGT) to find out whether an embryo has a genetic defect that might affect its ability to survive in the uterus or lead to health conditions once the embryo is a full-grown baby. This is done by removing a small number of cells from the trophectoderm of the blastocyst (Ie. the outer layer of cells of the blastocyst).
The DNA of those few cells is then multiplied to have a large enough sample of genetic material to “read” and then it is analyzed by genetic sequencing! Another development we have been able to make is to reduce the likelihood of multiple births. We realized that transferring one embryo decreases the chances of having multiple babies. Embryo grading systems are used in combination with PGT to know which embryos have a high chance of surviving in the womb. Embryos with the best chances of establishing a pregnancy will be transferred first.
The development of IVF is just a few of the discoveries and achievements in the field of reproductive medicine. There are a lot more, especially female scientists, that were essential to getting to where we are today. We can only hope that we continue to grow as a field and do our best to ensure infertile couples receive the treatment they desire and can finally hold their baby in their arms. Embryologists and medical professionals all across the field of reproductive medicine work to give parents that one beautiful moment that every mother and father dream of.
References:
Eskew, Ashley M, and Emily S Jungheim. “A History of Developments to Improve in vitro Fertilization.” Missouri medicine vol. 114,3 (2017): 156-159.
“The birth and history of IVF.” RMA Network
Image by Sarah Pflug
In reality, there is no normal!! The menstrual cycles and timing intercourse begins and ends with menstruation and is divided by ovulation into the follicular and luteal phases. The fertile window, during which there is a probability of conception from unprotected sex, is defined as the day of ovulation and the 5 days preceding it (the time window for sperm survival).
All available data suggests that there may be significant variability in fertile days- i.e.. not exactly 14 days before your next period!
We suggest tracking your basal body temperature AND your LH surge to determine your fertile days- and really try to determine if you are getting ovulation each month to time intercourse very well.
Late Ovulation
Late ovulation is when you ovulate (i.e. your ovary releases an egg) after day 21 of your menstrual cycle. Women with regular cycles consistently have periods every 21 to 35 days. … Very rarely, women have a normal 28-day cycle but ovulate around day 17, 18, or 19 instead of around day 14.
In true late ovulation, you will have a short luteal phase. Some doctors think that the uterus may not have enough time between cycles to build up its lining for an embryo to attach. That could theoretically lower your odds of getting pregnant, but it’s far from certain.
Any time your cycles are long and irregular, it’s a good idea to check in with your doctor to rule out PCOS, hyperprolactinemia or hypothyroidism. Getting treatment for these conditions can greatly increase your chances of getting pregnant and having a healthy pregnancy.
Azoospermia: TESE, MESA, and PESA
In some individuals, spermatozoa may not be present in the ejaculate. This condition is called Azoospermia. This can be either due to problems in sperm production itself or due to obstruction to the flow of semen during ejaculation. Reproductive tract obstruction can be acquired – as a result of infection, trauma, iatrogenic injury which can occur during bladder neck, pelvic, abdominal or inguino-scrotal surgery.
Congenital anomalies may be relatively uncommon in the general population, but can occur in up to 2 percent of infertile men. Best known condition is congenital bilateral absence of the vas deferens (CBAVD) which occurs in almost all men with cystic fibrosis.
Two techniques – Epididymal sperm retrieval & micromanipulation have revolutionized treatment of male infertility in the past decade. Men with congenital bilateral absence of the vas defences (CBAVD) or reproductive tract obstruction are now able to achieve pregnancies with use of these advanced techniques. You must know the normal Menstrual Cycles and Timing Intercourse.
PESA
PESA or Percutaneous Epididymal Sperm Aspiration (PESA), does not require a surgical incision. A small needle is passed directly into the head of the epididymis through the scrotal skin and fluid is aspirated. The embryologist retrieves the sperm cells from the fluid and prepares them for ICSI.
MESA
Microsurgical Epididymal Sperm Aspiration (MESA) is used in conditions like obstructive azoospermia, involving dissection of the epididymis under the operating microscope and incision of a single tubule. Fluid spills from the Epididymal tubule and pools in the Epididymal bed. This pooled fluid is then aspirated. Because the epididymis is richly vascularized, this technique invariably leads to contamination by blood cells that may affect sperm fertilizing capacity in vitro.
TESA and TESE
TESE or testicular sperm extraction is a surgical biopsy of the testis whereas TESA or testicular sperm aspiration is performed by inserting a needle in the testis and aspirating fluid and tissue with negative pressure. The aspirated tissue is then processed in the embryology laboratory and the sperm cells extracted are used for ICSI.
This is why you need to have ART Compass! Reagents traceability.
But wait, what is reagents traceability? You’ve come to the right place! Today we’re going to break down what that term means, why ART Compass enhances the ease at which it can be done, and why all of this matters in the first place.
What is reagent traceability?
It is crucial to monitor IVF lab solutions and apparatus. Some of the information that is important for IVF lab directors and staff is:
- Media name
- Manufacturer
- Lot number
- Date of receipt
- “In use” date
- Date of expiration
- Certificate of analysis
These data points must be tracked against patient cycles, so that the vessel and/or corresponding patients affected by a defect, manufacturer recall, etc can be discovered in a timely manner. Many electronic witnessing systems give this a cursory effort, but miss the mark by failing to correlate any of these data points with pregnancy outcomes. This is where laboratories are faltering.
Why is it important?
That’s a good question. These quality control measures have been established to ensure that the services a certain IVF lab is providing are of good quality. This is incredibly crucial! It is the lab’s job to ensure that the environment of the lab supports the growth of the embryo cultures. This is ensured by providing aseptic conditions for the embryos and also maintaining a safe work environment for the lab staff.
How does ART Compass help?
As we mentioned before many electronic witnessing systems give this a cursory effort, but miss the mark by failing to correlate any of the previously mentioned data points with pregnancy outcomes. ART Compass tracks all of the data points for true insight into patient outcomes. All of this information is in one place on a mobile device for easy access by the lab director and personnel! By forming this correlation, clinics are able to gather more information and really understand how exactly each feature of reagents‘ traceability affects pregnancy outcomes. Do a certain manufacturer’s products seem to be showing better results? Are there any expired reagents that are providing bad outcomes? If so, ART Compass highlights such errors and enables you to make the necessary changes required. Quality control is essential to any business, but in an IVF lab, there are literally lives depending on it.
A lab without ART Compass?
We’ve talked about what ART Compass can do for you, but let’s highlight what a clinic might be missing out on without the app! Undesirable outcomes when culturing embryos or regarding lab safety are already a hassle to deal with. Not knowing where they originated from? It just makes the whole problem worse! Let me outline some examples:
The manufacturer of a certain solution doesn’t seem to get it quite right. The solution was contaminated during the manufacturing process and has been used in several cultures for embryos. The cultures do not result in success and you would like to know why. However, tracing back the steps of multiple laboratory personnel isn’t only time consuming but almost impossible sometimes! It’s difficult to identify the source of these failed cultures.
A laboratory that does use our app?
Well, the app monitors the usage of all reagents! It then correlates such data to data regarding successful pregnancies. So you can easily trace back the cause of the failed cultures! By doing so you can quickly fix the issue and have things go back to normal.
As we said, an IVF lab is a complex setting with many moving parts. The ART Compass app can make the job easier for a lab director to have a birds-eye view of everything. All this information on a device at the touch of their fingertips! Lots of couples struggling with infertility heavily depend on IVF labs to be able to successfully carry out an IVF cycle. They trust that their IVF lab will incorporate the utmost precision and accuracy into their work. By making the job of the lab director easier (among other individuals), the ART Compass app hopes to create an environment where embryos can grow safely to eventually become a little bundle of joy for a couple.
References:
- Cutting R, Pritchard J, Clarke H, Martin K. Establishing quality control in the new IVF laboratory. Hum Fertil (Camb). 2004;7(2):119-125. doi:10.1080/14647270410001709188