The Journal of Clinical Embryology - Volume 9, Issue 4 - Winter 2006 by The Journal of Clinical Embryology™

The

Clinical Embryologist WINTER, 2006

Volume 9, Issue 4

The Clinical Embryologist is committed to reporting accurate, signiﬁcant and up-to-date information concerning issues of importance to clinical laboratory embryologists, andrologists and those professionals engaged in the science of human assisted reproductive technology (ART) and infertility medicine.

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The Clinical Embryologist

Volume 9, Issue 4

Editor’s Corner: “EmbryoSpeak”

TABLE OF CONTENTS

“And now, a word from the President!”

Editor’s Corner: “Embryospeak” Ken Drury, Ph.D...........................3

The Embryologist’s Choice for Prize Presentations ...................5 Interview with Dr. Joseph S. Sanfilippo, M.D. .....................7 Poster #P-144: Identification of Pregnancy Associated Transcripts in Human Cumulus Cells Using Affymetrix Genechip Technology A.M. Kocabas, J. Crosby, G.J. Rosa, E. Fernandez, J.B. Cibelli ............11

Poster #O-15: Anovulation May Be A Risk Factor for Major Birth Defects In Children Born After Infertility Treatment B.J. Van Voorhis, A.E. Sparks, C.H. Syrop, C.S. Sipe, G.L. Ryan, A. Dokras ..............13

The Computer Savvy Embryologist..........................15 Graduate Degree Programs for Clinical Embryologists.....27 Meetings for the Embryologist..........................28 Opinions expressed in each article are solely those of each signatory of that article and so may not or do not reflect the opinions of any unsigned Editorial Board member nor -- unless he is an explicit signatory -- of the Editor and/ or the Publisher.

Ken Drury, Ph.D., Editor

t’s not often that the President has time to speak directly to a clinical embryologist. His time is usually taken with high level cabinet ministry meetings and strategy conferences of international consequence. But in this issue we hear directly from the man himself, Dr. Joseph S. Sanﬁlippo, this year’s president of the American Society of Reproductive Medicine (ASRM), presiding over the Annual Conference here in New Orleans. You will hear ﬁrst hand how this year’s meeting overcame many obstacles. As you may have suspected, this issue of The Clinical Embryologist will highlight those portions of the ASRM annual meeting that focused on issues relevant to our fellow ART laboratory colleagues. In this day and age, no one individual can attend the vast number of presentations available for any one subject, let alone spend time with friends, venders, and enjoy the wine and cheese refreshments, while inspecting over 1000 posters. I admit that I felt faint when I entered the poster session and immediately encountered the heat of information emanating from each posted abstract. Happily,

the editorial board members have come to the rescue, and having searched though the presentations, offer you critical information you may have missed. Being the recipient of a prize winning presentation is very rewarding but it usually happens to someone else. However, the real winner in this case is that person who can come away from a conference like ASRM having found the true meaning of science in the IVF laboratory. If you didn’t come away with that feeling, instead of Alka-Seltzer, we recommend that you review those oral and poster presentations that are highlighted in this issue. There are five oral and six posters abstracts that we think are worthy of a second look. Among these presentations you will find a common theme developing which The Clinical Embryologist will explore further in its first issue of 2007. This theme will encompass the utilization of non-invasive embryo viability monitoring systems, and how these new technologies might assist in determining which embryo has the best chance of contributing to a successful IVF outcome. In other words: “What’s in your mass spect?” ■

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The Clinical Embryologist

Volume 9, Issue 4

The Embryologist’s Choice for Prize Presentations Within a large and diverse organization such as the American Society of Reproductive Medicine (ASRM), abstracts chosen for presentation and special recognition may not always be those of interest, or of use, to the Clinical Embryologist and others laboring in the ART Laboratory. Below is a sampling of presentations (both oral and poster) which the Clinical Embryologist would like to highlight for its readers. O-100

O-205

IMPROVED BLASTOCYCST DEVELOPMENT WITH MICROFLUIDICS AND BRAILLE PIN ACTUATOR ENABLED DYNAMIC CULTURE.

NON-INVASIVE, REAL-TIME RESPIRATIONS MEASUREMENTS OF HUMAN OOCYTES AND EMBRYOS: A FUTURE MEANS OF EMBRYO

L.M. Cabrera, Y.S. Heo, J. Ding, S. Takayama, G.D. Smith.

SELECTION? L. Scott A. Finn. K. DeLegge, J. Hill, N. Ramsing

O-134 RELATIONSHIP BETWEEN EMBRYONIC SECRETOME AND CHROMOSOMAL ABNORMALITIES IN HUMAN IVF.

P-14

M.G. Katz-Jaffe, J. Stevens, W.G. Kearns, D.K. Gardner, W.B. Schoolcraft

RESULTS IN IMPROVED ART OUTCOMES

SOLUBLE HLA-G (SHLA-G) EXPRESSION FROM TRANSFER OF MORPHOLOGICALLY NORMAL EMBRYOS WITH A HIGH

O-138

GRADUATED EMBRYO SCORE (GES): A MOVE

PREIMPLANTATION GENETIC DIAGNOSIS (PGD) IS INDICATED FOR RECURRENT MISCARRIAGE EVEN IN CYCLES PRODUCING FIVE OR FEWER EMBRYOS.

TOWARD SINGLE EMBRYO TRANSFER. J.D. Fisch, G. Sher

J. Garrisi, S.H. Chen, N.A. Cekleniak, M.G. Garrisi, J. Cohen, S. Munne

P-127 CLINICAL SIGNIFICANCE AND PREDICTIVE

O-151

VALUE OF THE HYALURONON BINDING

PRESENCE OF MEIOTIC SPINDLE PREDICTS EMBRYO COMPETENCE FOLLOWING OOCYTE CRYOPRESERVATION.

ASSAY (HBATM) IN INVITRO FERTILIZATION (IVF). K.C. Worrilow, H.T. Huynh, J.B. Bower, A.J. Peters,

N. Noyes, H.C. Chang, H. Liu, P. Labella L. Meng, J.A. Grifo

J.B. Johnston

The Clinical Embryologist

Volume 9, Issue 4

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The Clinical Embryologist

Volume 9, Issue 4

Interview with Dr. Joseph S. Sanfilippo, M.D.

President of the American Society of Reproductive Medicine ASRM Annual Meeting in New Orleans Interviewed by Kenneth C. Drury, Ph.D., Editor, The Clinical Embryologist

the hurricanes did hit the New Orleans area and the convention site was very much in question. However, there was such a commitment from the people in public relations, the convention bureau, and other officials, and everyone made a sincere effort of assuring us that holding the meeting here would be in all our best interests. Indeed, without any exception since we have come here, the people attending this meeting keep making it a point of thanking us for making the decision to stay in New Orleans. We are very proud to work with the local individuals through out the City. A great example of this occurred during the opening ceremony where we had nine restaurants, all of which agreed to participate in our opening ceremony, each highlighting the cuisine for which they are so well known. That helped launch this program on the right foot and all those in attendance remarked about what a great opening reception it was and that it truly highlighted New Orleans’ superb cuisine and hospitality.

r. Sanfilippo, it’s a pleasure speaking with you today on behalf of The Clinical Embryologist. Let’s touch on a few issues concerning the American Society of Reproductive Medicine; its present state; the direction in which it’s moving; how special interest groups interact and how you see this Society in a few years down the road. So, let me begin by asking:

Q: How many years of advance preparation does it take to produce a conference of this size and complexity? A: At present, we are now thinking about the year 2013, so obviously these programs are planned significantly in advance of the actual event. There is a scientific program committee, where a given individual runs specific segments of the program and subsequently moves up the ladder to become the overall general program chair. This is spread out over a number of years. So, there is a learning curve of several years that is perquisite to any given individual putting the entire program together.

Q: As we know, the Society deals with reproductive medicine and that may, or may not, say exactly what the Society is all about. There are many diverse programs active within the Society. How does the Society, as a whole, cater to these differing programs which may themselves have very diverse philosophies of their own?

Q: This last year there was some controversy about actually proceeding with and conducting the conference here in New Orleans due to the disastrous consequences of hurricanes Rita and Katrina. How do you feel about the decision to actually go ahead with the original conference plan at this point?

A: A number of years ago the decision was made to first have affiliate societies, as in sub-societies, and then have these focus on areas such as assisted reproductive technology (SART) , reproductive surgery (SRS), reproductive endocrinology and infertility (SREI) , male reproduction and urology (SMRU), basically andrology and urology together, and many others. Also, a decision was made that we should further cater to the questions you are asking about, and that is, developing special interest groups and professional groups, and that there be

A: I’m very proud that we made the decision for the conference to remain in New Orleans. As a matter of fact there was another large convention that was supposed to co-occupy this convention center but in the end elected not have their convention here. We felt a commitment to the people of the city of New Orleans and we felt a commitment to honor our signed contractual agreement to hold our convention here if at all possible. Unfortunately,

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Volume 9, Issue 4

specific criteria met in order to become a special interest or professional group. The bottom line is that our efforts to allow people to network, to have a special interest on whatever the topic might be, Reproductive Biology Professional Group (RBPG) and the Reproductive Laboratory Technology Professional Group (RLTPG) to name a few, benefit the entire society. We also have international sectors, and these are each headed by a chair, and it’s an opportunity to have papers presented and to conduct business meetings and come up with interactive projects that can be presented at a subsequent annual meeting. This represents a joint effort for all of us to work together in whatever the particular area of interest may be.

because that doesn’t serve the right purpose. Q: I think that brings us to a point where we can see that this type of an organization, these types of special interest interactions, take a large investment of resources to support the various interactive groups and allow them to work toward their respective goals. Societal dues are one way of trying to make these resources available, but at the same time, dues by themselves cannot support all these demands. The pharmaceutical industry has, in the past, been a very large source of support, but, when it comes to the basic sciences and research, the government seems to have a very limited sense of what the resource requirements are; especially concerning human reproduction. How is this society poised to meet the resource needs of the basic sciences?

Q: So, at this point, the ASRM primarily holds these various groups together in an effort to move in an organized manner rather than splitting apart and having these “special interest groups” simply follow their own agendas?

A: Well, the society has several means of addressing this question. The first of which is to have collaborative conferences preceding this annual meeting. The NIH, ASRM, collaborative symposium focused this year on endometriosis. Immediately following this will be an NIH/ASRM collaborative program which will address premature ovarian failure, so this is an effort for us, ASRM, to work with the NIH to exchange ideas and obtain committed resources. We work also with industry to identify individuals who are interested in conducting research within a particular area, and be recipients of funding; here contraception comes to mind. We work with industry to educate our residents; there’s a resident reporter program in place. The NIH works very closely, in a collaborative effort, with our executive director in order to exchange ideas. They come to ASRM and we help them identify people who are authorities in a particular field. Really, it’s a truly collaborative effort that also includes educating the legislators who vote on relevant funding issues. Our Washington lobby keeps their finger on the pulse, and makes every effort to maximize research dollars that become available and that translates to all levels of research. Even though there is limited funding, the hope is that with the education of legislators, they will realize the importance of the research that takes place in this society and they can come to our aid and support and allow us to continue the research that is part and parcel so integral to reproductive medicine.

A: ASRM is one of the very few societies that is growing in membership and I attribute this to the fact that people can come to this meeting and exchange ideas and learn the latest cutting edge research, as well as, network in their interest groups. Just today, I received a bulletin that allows a clinician to convey to their patients how to identify a geneticist in their local area. There are also other things, such as working with the FDA concerning laboratory regulations, and how we can have a voice in guiding that process. This all happens through the coordinated efforts of those who participate in the special interest groups and the professional groups. They all have a voice. ASRM also has an individual who is housed in Washington D.C. and participates in congressional activities, all of which are designed to ensure that we have a role in educating legislators and assisting them in making informed decisions on regulations governing reproductive medicine. Just today, we had a meeting of the chairs of special interests and professional groups and the point is, that as a society, we want to know how can we reach out, how can we move to the next level with increasing support and provide for the wants and needs of all groups within the Society. So, again, the concept to me is we are going to make more progress by joining together, having a unified approach, than by trying to split the Society apart

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Volume 9, Issue 4

education, to provide better patient care, to work closer with individuals in Washington, D.C. and know what the issues are and learn about them as soon as they are put on the table so that, we as a society, can respond to concerns that affect any aspect of reproductive medicine. So, briefly, that would be my advice to the incoming president.

Q: Let me ask you what will you advise the incoming president elect? A: The incoming president elect is a very well prepared individual because he has come up the presidential chain and has already been responsible for many of the functions of the society. This individual, Dr. Steve Ory, has been privy to all of the activities of the society. The advice to him is to be sure that the current established initiatives are brought to the next level. My second point of advice is to get out to the people of this society, the members, and find out their wants and needs and to work with all of the professional and special interest groups as closely as possible, because itâ&#x20AC;&#x2122;s you, members of these affiliate and sub-societies, that constitutes where the action is. We need to know what you need to enhance your

Q: To conclude this interview, what would you like to say to the readers of The Clinical Embryologist, those in the laboratory, those people putting together new technologies to advance the science of reproductive medicine? A: I would like to say, for those past presidents and future presidents, thank you, and thank you for your commitment and expertise, your research knowledge, bringing us to where we are today. Continued on Page 25

The Clinical Embryologist

Volume 9, Issue 4

Poster #P-144:

Identification of Pregnancy Associated Transcripts in Human Cumulus Cells Using Affymetrix Genechip Technology A.M. Kocabas, J. Crosby, G.J. Rosa, E. Fernandez, J.B. Cibelli

we will do IVF cases in the future and optimize the outcome for patients. At this point, the authors have no idea what the functional roles are for the genes that are being over expressed in the cumulus cells from developmentally competent eggs; but frankly, that really doesn’t matter if the proteins are to be used simply as markers of viability. I believe the scientiﬁc community in general also feels this is a unique study as it has recently been published in part in PNAS (Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14027-32. Epub 2006 Sep 12.). ■

his study was designed to look for differentially expressed genes in cumulus cells from developmentally competent and non competent oocytes with a goal of identifying marker genes associated with eggs that result in ongoing human pregnancies. No such study has ever been attempted. Only the link between expression of marker genes and oocyte maturation has been demonstrated to date. By linking gene expression not only to oocyte maturation, but also to embryonic development, implantation and pregnancy, this study is quite unique. Cumulus cells were obtained from the OCC during conventional IVF treatment and sent to the lab for study. The cells were lysed and the isolated RNA subjected to PCR and T7 based amplification. Amplified cDNA was used to create antisense markers for RNA and placed on Affymetrix (Santa Clara, CA) gene chips for analysis. The authors identified 503 differentially produced genes associated with developmental competence and embryonic viability/ implantation, providing the FIRST comprehensive baseline for the genes linked to a pregnancy competent IVF cycle. At the presentation of the posters, the authors presented new data showing they had found four genes that were consistently over expressed in pregnancy related cycles that hold promise for commercial development as biomarkers which can be used to select eggs for IVF from the pool of harvested oocytes, a priori allowing the lab to focus its efforts only on those oocytes that express the genes that indicate pregnancy potential. My feeling was that this study was very unique in that it tests for developmental competency well before an embryo is even created in vitro. Unlike the recent emphasis on genetic evaluation of the secretome (very vogue these days it seems) this paper provides the basis for a future lab test that would advance the selection by days, doing it at the level of the gamete, not the embryo. Thus, I feel this study is offering a potential major advance in how

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The Clinical Embryologist

Volume 9, Issue 4

Poster #O-15:

Anovulation May Be A Risk Factor for Major Birth Defects In Children Born After Infertility Treatment B.J. Van Voorhis, A.E. Sparks, C.H. Syrop, C.S. Sipe, G.L. Ryan, A. Dokras

s clinical embryologists, we are relentless in our pursuit of equipment, methods and supplies that enhance outcome and at least equally diligent in our search for things in our purview that might thwart safety and success. We collectively spend thousands of man-hours and hundreds of thousands of dollars on quality control procedures aimed at eliminating compromised outcomes due to sub-par media, dishes, gases, as well as laboratory environmental conditions such as air quality, lighting, temperature, etc. What we rarely do is look at the most obvious variable - the patient. Recently, the reproductive group from the University of Iowa reported a signiﬁcant increase in the rate of major birth defects from IVF, a ﬁnding of concern to all of us, particularly in light of the putative role of the laboratory in altering epigenesis. This same group of Van Voorhis, Sparks, Syrop, Sipe, Ryan and Dokras had abstract O-15 at the recent ASRM meeting entitled “Anovulation may be a risk

factor for major birth defects in children born after infertility treatment”. A retrospective analysis of 1805 infants born to 1134 women using a generalized logit model to identify risk factors, followed by multi-factor analysis, indicated that high order multiple gestations, male gender and the combined diagnostic categories of ovulatory factor/polycystic ovarian syndrome were significant for major birth defects. Of interest was the finding that 13% of 73 infants born to mothers with a definite diagnosis of PCOS had major birth defects with an odds ratio of 2.53. As indicated by the authors, this is the first study to link birth defects with a maternal infertility diagnosis. This is of further surprise considering that nearly two million IVF babies have been born worldwide and a striking example that we often look past the obvious in our analytical activities. ■

Critique by Thomas B. Pool, Ph.D. HCLD rpool@fertilitysa.com

INTERNATIONAL SUBSCRIPTION TO

The Clinical Embryologist

The Clinical Embryologist is pleased to announce that future issues will now be available internationally. This increase in circulation will bring wider coverage for articles submitted to our journal, as well as broaden the source of important research taking place around the world. In order to make this possible, we will be charging a nominal subscription fee of US$30.00 per year, for four issues, to cover shipping and handling. We hope this will meet the needs of our colleagues overseas. A subscription form will be made available. Please refer to our website for further information on how to subscribe through the internet. http://www.embryologists.com.

The Clinical Embryologist

Volume 9, Issue 4

The Computer Savvy Embryologist

re Clinical Embryologists computer savvy? This is an easy question to answer; Yes. Even if we didn’t take credit earning courses in information technology and computer science, the vast majority have mastered those software and hardware issues that are necessary in order to operate a state of the art ART laboratory. But how much knowledge and expertise is required to maintain a SART/CAP accredited laboratory? The following requirements are features of the most recently issued CAP general laboratory checklist (4/06/2006) which may pose a multitude of frustrating problems to embryology/andrology laboratory directors and supervisors. To many, these requirements may seem to be over- kill. However, with every new technology (which is supposed to make life easier and less complicated) we inevitably find new issues that require, at least initially, a significant amount of invested attention and energy in order to ensure proper functioning. The following list presents a few CAP inspection checks with which the ART laboratory must now contend. With these new requirements placed on the laboratory, we might well contend that additional information technology trained personnel be employed to address these highly technical non-ART issues. The check lists presented are all Phase II deficiencies which the lab can not ignore. For the full list of General Laboratory required checks see the following web link: http://www.cap.org/apps/docs/laboratory_accreditation/checklists/laboratory_general_april2006.doc (See pages 63-84) Remember that the FDA will also want to weigh-in once sub-part D of Part 1271 (Current Good Tissue Practice) is enacted.

GEN.42950

Phase II

N/A YES NO

Are LIS/computer procedures clearly documented, complete and readily available to all authorized users? NOTE: Procedures should be appropriate to the level of use of the system, and must encompass the day-to-day activities of the laboratory staff as well as the daily operations of the Information Technology staff. It is not required for all procedures to be kept in a single manual, as long as the users have access to the procedures they need to perform their job duties. Current practice must match policy and procedure documents.

**NEW** GEN.42975

03/30/2005 Phase II

N/A YES NO

Is there a procedure for the support of the computer system? NOTE: The laboratory must have a procedure outlining the support of the system, including local maintenance, vendor support and emergency contact information. Continued on Page 19

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The Clinical Embryologist

Volume 9, Issue 4

The Computer Savvy Embryologist Continued from Page 15

**NEW** GEN.43011

03/30/2005 Phase II

N/A YES NO

Is there documentation of all hardware modiﬁcations?

GEN.43022

Phase II

N/A YES NO

Is there documentation that programs are adequately tested for proper functioning when first installed and after any modifications, and that the laboratory director or designee has approved the use of all new programs and modifications? NOTE: Computer programs must be checked for proper performance when first installed and after any changes or modifications. Any changes or modifications to the system must be documented, and the laboratory director or designee must approve all changes, additions and deletions in programs, the test library, and major computer functions before they are released. Documentation must be retained for at least two years beyond the service life of the system.

DOES EVERYONE AT YOUR FERTILITY CENTER RECEIVE THE CLINICAL EMBRYOLOGIST? New recipient or new address NAME: ____________________________________________________________________________________________________ ADDRESS: _________________________________________________________________________________________________ CITY:______________________________________________________________________________________________________ STATE:_______________________________

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PHONE: ________________________________________________ FAX: _____________________________________________ EMAIL: ____________________________________________________________________________________________________ Photocopy this block and fax with completed full address to (352) 331-6250 or e-mail this full address information to: embryospeak@bellsouth.net.

The Clinical Embryologist

GEN.43088

Volume 9, Issue 4

Phase II

N/A YES NO

Is there a documented process to verify the integrity of the system (operating system, applications and database) after restoration of data files? NOTE: The computer system must be checked after restoration of data files to ensure that no inadvertent alterations have occurred that might affect clinical result reporting. The integrity of the system may be verified, for example, by review of a representative number of computer-generated patient reports, or by generating test (“dummy”) patient reports for review. The laboratory director is responsible for determining verification procedure(s) appropriate to the laboratory. Whether or not the data center is located on site, all facilities served by the data center must participate in the verification of the system(s) integrity following a hardware or software failure.

GEN.43132

Phase II

N/A YES NO

Is there evidence of ongoing evaluation of system maintenance records? NOTE: Hardware manufacturers have a standard maintenance schedule that must be documented, similar to laboratory instrument maintenance. In addition, regularly scheduled maintenance must be documented for printers (cleaning, other service records).

GEN.43150

Phase II

N/A YES NO

Are there explicit documented policies that specify who may use the computer system to enter or access patient data, change results, change billing or alter programs? NOTE: Policies must deﬁne those who may only access patient data and users who are authorized to enter patient results, change results, change billing, or alter computer tables or programs.

**REVISED** GEN.43200

03/30/2005 Phase I

N/A YES NO

Are computer access codes (security codes, user codes) in place to limit individuals’ access to those functions they are authorized to use, and is the security of access codes maintained (e.g., inactivated when employees leave, not posted on terminals)? NOTE: The laboratory should establish security (user) codes to permit only speciﬁcally authorized individuals to access patient data or alter programs. A system that allows different levels of user access to the system based on the user’s authorization is desirable and usually provides effective security. Examples of best practices include these requirements: periodic alteration of passwords by users; minimum character length for passwords; password complexity requirements (e.g., a combination of alphanumeric characters); recording of failed log-on attempts with user lock-out after a deﬁned number of unsuccessful log-on attempts.

The Clinical Embryologist

GEN.43387

Volume 9, Issue 4

Phase II

N/A YES NO

Does the laboratory have procedures to ensure compliance with HIPAA? NOTE: The Health Information Portability and Accountability Act (HIPAA) is a federal law requiring protection of patientsâ&#x20AC;&#x2122; health care information. The law requires maintenance of conďŹ dentiality when patient data is transmitted between two organizations. Also, organizations must establish appropriate relationships between sender and receiver of patient data to ensure that the information will be used as intended. The laboratory must periodically monitor compliance with HIPAA.

**REVISED** GEN.43450

03/30/2005 Phase II

N/A YES NO

Is there documentation that all calculations performed on patient data by the computer are reviewed annually, or when a system change is made that may affect the calculations? NOTE: Errors can be inadvertently introduced into established computer programs. Calculations, algorithms, and/or rules involving reportable patient results must be rechecked and documented to ensure accuracy.

The Clinical Embryologist

GEN.43800

Volume 9, Issue 4

Phase II

N/A YES NO

Is there an adequate system to identify all individuals who have entered and/or modified patient data or control files? NOTE: When individual tests from a single test order (e.g., multiple tests with same accession number) are performed by separate individuals and the test result is entered into the LIS, the system must provide an audit trail to document each person involved. For example, a single accession number having orders for electrolytes and a lipid panel may have testing done by two or more individuals. The laboratory should be able to identify the responsible personnel who performed each test and posted the data. This includes sequential corrections made to a single test result. If autoverification is used, then the audit trail should reflect that the result was verified automatically at a given time.

GEN.43825

Phase II

N/A YES NO

Are manual and automated result entries verified before final acceptance and reporting by the computer? NOTE: Data entered into the computer system either manually or by automated methods must be reviewed by an authorized individual who verifies the accuracy of the input data before final acceptance and reporting by the computer. An example of best practices for this step is checking the result against the reportable range and critical values for the test. Depending on the local environment, this may or may not require a second person. Verification procedures must generate an audit trail.

GEN.43946

Phase II

N/A YES NO

Are there documented procedures for the preservation of data and equipment in case of an unexpected destructive event (e.g., fire, flood), software failure and/or hardware failure, and do these procedures allow for the timely restoration of service? NOTE: These procedures can include (but are not limited to) steps to limit the extent of the destructive event, protocols for periodic backing up and storing of information, procedures for off-site storage of backup data, and protocols/procedures for restoring information from backed up media. The procedures should specifically address the recoverability of patient information. Changes to hardware and software commonly require review and reevaluation of these documented procedures. These procedures must specifically address the physical environment and equipment. This checklist question is often addressed by the organization’s disaster plan.

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The Clinical Embryologist

GEN.44100

Volume 9, Issue 4

Phase II

N/A YES NO

Are computer error messages that alert computer users of imminent problems monitored and is the error message response system tested periodically? NOTE: Computer error messages come in many forms, and usually signify an event that requires immediate attention to rectify a situation. Examples of error messages include system errors, low disk space warnings, database validation errors, exceeding environmental limits, etc. There should be a person responsible for acknowledging the message, a deﬁned system of notiﬁcation, and response to the situation. The error message response process needs to be periodically tested. GEN.44150

Phase II

N/A YES NO

Is there documentation of responses to any error messages during the system backup?

GEN.48500

Phase II

N/A YES NO

Is there a documented system in operation to periodically verify that patient results are accurately transmitted from the point of data entry (interfaced instruments and manual input) to all types of patient reports (both paper and video displays)? NOTE: This includes evaluation of data transmitted from the LIS to other computer systems and their output devices. Reference ranges and comments, as well as actual patient results, must be evaluated. When multiple copies of tables are maintained within more than one computer system, they must be periodically compared to ensure consistency among all copies in use.

This checklist question applies only to interfaces through which laboratory information systems directly send or receive data. For example, if the laboratory information system is interfaced with the hospital information system, the laboratory must verify the accuracy of patient results transmitted across the interface between the two systems. However, the checklist question would not apply to data transmitted from the hospital information system to a physician ofﬁce information system. ■

The Clinical Embryologist

Volume 9, Issue 4

Interview with Dr. Joseph S. Sanfilippo, M.D. Continued from Page 9

As far as I’m concerned, the credit goes to you who are there 24/7 working with your colleague physicians, Ph.D.s; individuals who have learned to listen to your recommendations and your suggestions. I want to say that my personal experience, working with those people in our andrology and embryology labs, that I have always looked forward to coming to them and saying “here is the problem, what do you think?”. We have direct embryologist’s input in patient management. When it comes to Andrology, I’m always open to suggestions; open to new concepts for either research ideas or to what we can do for this particular patient at hand. The bottom line

is communication. I think it is so important that the team has a mechanism established to assure that everyone is working together. Embryologists, andrologists, the people who head up IVF units, the directors of reproductive endocrinology, nurses, we all have special expertise that must be employed to assure that our patients receive the best care possible. I always go back to the old adage, “it’s all in the communication”. Dr. Sanfilippo, thank you very much for spending time speaking with the readers of The Clinical Embryologist. ■

Support The Clinical Embryologist The Clinical Embryologist is a nonpartisan, specialized publication dedicated to the dissemination of shared best practices and issues of interest for professionals in the ﬁeld of human assisted reproduction. It has served this mission for the past nine years, enriching the professional lives and improving the technical competence of thousands of these fertility laboratory practitioners, -- initially in the United States; increasingly all over the world. With your support, The Clinical Embryologist can continue broadening the perspectives and providing current practical information for the beneﬁt of clinical embryology laboratory personnel. Supporting The Clinical Embryologist will help bring the most up-to-date information that embryologists need and use on a daily basis to your IVF laboratory. Your support also helps The Clinical Embryologist supply a variety of educational and outreach services tailored to the IVF community. We are expanding our coverage and need your contribution. Individual donations from readers like you constitute an important source of funding for us. To make your donation, ($10,$15,$20,$25), Please

Simply call us toll free at 1-800-820-3029. [We accept credit cards or will be happy to bill you directly at your home or ofﬁce.] Thank you very much, The Publisher www.embryologists.com

THE RESULTS ARE IN.

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The Clinical Embryologist

Volume 9, Issue 4

Graduate Degree Programs for Clinical Embryologists 1. The Eastern Virginia Medical School M.S. in Biomedical sciences – Clinical Embryology and Andrology http://www.evms.edu/hlthprof/embryology/ index.html

4. Northwestern University Program in Clinical Embryology, Master of Science Degree http://www.tgs.northwestern. edu/academics/schooloverview/feinberg/ embryology

Director of Enrollment for Health Professions Attention: Clinical Embryology & Andrology Program Eastern Virginia Medical School Lewis Hall, Suite 1100 700 W. Olney Road Norfolk, Virginia 23507-1607

John X. Zhang, Director Program in Clinical Embryology Department of Obstetrics and Gynecology Feinberg School of Medicine 333 East Superior Street, Suite 490 Chicago, Illinois 60611 x-zhang3@northwestern.edu phone: 312-695-7773

2. Centre of Reproduction and Development at the Monash Institute of Medical Research: Master’s of Clinical Embryology http://www.med.monash.edu.au/eprb/ courseinfo/masterclin.html

5. The ACE Post Graduate Certiﬁcate in Clinical Embryology, UK http://www.embryologists.org.uk/education/

The Course Manager Education Program in Reproductive Biology Postgraduate Course Administrator Education Program in Reproductive Biology C/-- Monash Institute of Medical Research 27--31 Wright Street Clayton, Victoria 3168 Australia Tel. +61 3 95947360 Fax. +61 3 959473114 Email: eprb@med.monash.edu.au Web Site: www.med.monash.edu.au/eprb/

ACE Training Certiﬁcate Secretariat Dave Cole, ACE Membership Ofﬁce 82A High Street Sawston Cambridge, CB2 4HJ 6. The University of Kentucky Masters of Science in Clinical Sciences: Reproductive Laboratory Science http://www.mc.uky.edu/cls/RLS/RLS_Opening_ Page.htm

3. University of Leeds, UK MSc / Diploma in Clinical Embryology http://www.clinicalembryology.net/

Linda S. Gorman, Ph.D., Director of Graduate Studies-Reproductive Laboratory Science Program Clinical Sciences Graduate Program University of Kentucky 900 S. Limestone Room 209 Lexington, Kentucky 40536-0200

Miss Alexandra Tasker – Obstetrics & Gynaecology, Level D, Clarendon Wing, Leeds General Inﬁrmary, Leeds, LS2 9NS; Tel 0113 392 8170; Fax 0113 392 6021; E-Mail: a.j.tasker@leeds.ac.uk

The Clinical Embryologist

THE CLINICAL EMBRYOLOGIST EDITORIAL BOARD Barry D. Bavister, Ph.D. Department of Biological Sciences University of New Orleans New Orleans, LA 70148-2960 504-280-6196 bbaviste@uno.edu Carol Brenner, PhD Department of Biology University of New Orleans 985-789-5685 (Cell) cbrenner@uno.edu

Volume 9, Issue 4

Meetings for the Embryologist (Please send meetings you would like to see included in this listing) 1.

Dates: January 3-7, 2007 Place: Puerto Rico, The Westin Rio Mar Golf and Beach Resort, Rio Grande, Puerto Rico 1.8 CEUs - Approved Contact: Laurie Ferrara, Email: lferrara@embryos.net 2.

and September 15-18 2007, Boston, MA Watch the website at www.aatb.org for additional information. 3.

Kenneth C. Drury, Ph.D. HCLD Editor embryospeak.bellsouth.net 352-331-5235 Fred M.W. Zander Publisher 352-331-5235 embryospeak@bellsouth.net

American Society of Andrology (ASA) ASA 32nd Annual Conference April 18-24, 2007, Hyatt Regency Tampa 211 North Tampa Street

Thomas B. Pool, Ph.D. HCLD Fertility Center of San Antonio San Antonio, TX 210-614 3232 rpool@fertilitysa.com Richard G. Rawlins, Ph.D. HCLD Rush Centers for Advanced Reproductive Care Dept OB/GYN Rush Medical Center 1653 W. Congress Parkway Chicago, IL 60612 312-942 2152 Richard_G_Rawlins@rush.edu

American Association of Tissue Banks (AATB) March 25-27 2007, Hollywood, CA

Kathryn J. Go, Ph.D. HCLD Reproductive Science Center One Forbes Road Lexington, MA 02421-7305 kathy.go@integramed.com David L. Hill, Ph.D. HCLD ART Reproductive Center Beverly Hills, CA 310-246-2417 embryonics@adelphia.net

A Review of Preimplantation Embryology

Tampa, Florida P: 813-225-1234 http://www.andrologysociety.com/meetings/future.aspx 4.

PCRS 2007 Description: PaciďŹ c Coast Reproductive Society Dates: April 18-22, 2007 Place: Rancho Mirage, CA, USA Contact: Web Site: http://www.pcrsonline.org

American Association of Bioanalyts (AAB) and the College of Reproductive Biologists (CRB) annual Meeting and Educational Conference May 17-19, 2007 Rosen Centre Hotel, Orlando, Florida http://www.aab.org/conf%202007.htm

The Clinical Embryologist

Volume 9, Issue 4

Frontiers in Reproduction: Molecular

Featured Website:

& Cellular Concepts

Dates: May 6 - June 16, 2007

Protocols for Human Oocyte and Embryo

Place: Marine Biological Laboratory (MBL),

Cryopreservation

Woods Hole, MA, USA

By Michael Tucker, Ph.D., HCLD

Contact: Web Site: http://ﬁr.MBL.edu

http://www.ivf.com/boston.html

Gordon Conference: FERTILIZATION & ACTIVATION OF DEVELOPMENT

INSTRUCTIONS FOR AUTHORS

July 15-20, 2007 Holderness School, Plymouth, NH Fertilization, the fusion of a sperm with

E-mail articles as Word documents, double-spaced, in

an egg, initiates the development of a new

any ART journal format, with all authors’ professional

individual. There are many critical processes

affiliations and e-mails. FAX or mail signed compliance

that culminate in fertilization, including

with conventional standards of authorship and

meiotic maturation, cell motility, cell-cell

originality. Minimal illustrations. Keep paragraphs short.

recognition, exocytosis, cell-cell fusion, and

Skip 2 spaces between sentences. Articles 1,500-3,000

the activation of the zygote. This conference

words (6-12 pages), shorter for abstracts, lab tips and

will bring together junior and senior scientists

letters (signed, return mail and e-mail addresses). Next

from various regions of the world; from

article due date: February 16, 2007 for Vol. 10, Issue 1.

academic, governmental, and industrial

Email to: embryospeak@bellsouth.net

sectors; and with wide-ranging experimental

Office Phone: (352) 331-5235

approaches to discuss recent advances and to consider present challenges in understanding these processes. It is anticipated that, in addition to model organism studies promoting

NOTE TO ADVERTISERS

a greater understanding of the basic biology of fertilization and early development, the healthrelated beneﬁts and applications in wildlife

Please observe that 2006 advertising rates remain the

conservation will be integrated into the

same as 2005. Prepayment for 4 issues will reduce those

discussions of the conference. In addition to

fees by 5%. For more information, please contact the

platform presentations, panel discussions and

Clinical Embryologist advertising office:

poster sessions will be scheduled to increase ceadvertising@bellsouth.net • (352) 331-5235

the interactions among participants.

— The Publisher

Program Chair: George L Gerton GERTON@MAIL.MED.UPENN.EDU

FOR SUBCUTANEOUS OR INTRAMUSCULAR USE ONLY BRIEF SUMMARY Please see package insert for full prescribing information. INDICATIONS AND USAGE Follistim® AQ (follitropin beta injection) is indicated for the development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology (ART) program. Follistim® AQ is also indicated for the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure. Selection of Patients Before treatment with Follistim® AQ is instituted: 1. A thorough gynecologic and endocrinologic evaluation of the patient must be performed. The evaluation should include a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of reviewing a patient’s history, performing a physical examination, determining serum hormonal levels as indicated, and optionally performing an endometrial biopsy. Patients with tubal pathology should receive Follistim® AQ only if enrolled in an ART program. 2. Primary ovarian failure should be excluded by the determination of circulating gonadotropin levels. 3. Careful examination should be made to rule out early pregnancy. 4. Evaluation of the partner’s fertility potential should be included in the workup procedure. CONTRAINDICATIONS Follistim® AQ (follitropin beta injection) is contraindicated in women who exhibit: 1. Prior hypersensitivity to recombinant hFSH products. 2. High levels of FSH indicating primary ovarian failure. 3. Uncontrolled thyroid or adrenal dysfunction. 4. Tumor of the ovary, breast, uterus, hypothalamus or pituitary gland. 5. Pregnancy. 6. Heavy or irregular vaginal bleeding of undetermined origin. 7. Ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS). 8. Hypersensitivity reactions to streptomycin or neomycin. Follistim® AQ may contain traces of these antibiotics and may cause hypersensitivity reactions in susceptible persons. WARNINGS Follistim® AQ (follitropin beta injection) should be used only by physicians who are experienced in infertility treatment. Follistim® AQ is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) (see WARNINGS-Overstimulation of the Ovary During Follistim® AQ Therapy) with or without pulmonary or vascular complications (see WARNINGS-Pulmonary and Vascular Complications) and multiple births (see WARNINGS-Multiple Births). Gonadotropin therapy requires the availability of appropriate monitoring facilities (see PRECAUTIONS-Laboratory Tests). Overstimulation of the Ovary During Follistim® AQ Therapy In order to minimize the hazards associated with the occasional abnormal ovarian enlargement that may occur with Follistim® AQ therapy, the lowest effective dose should be used (see DOSAGE AND ADMINISTRATION in the full prescribing information). Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels can further minimize the risk of overstimulation. If the ovaries are abnormally enlarged on the last day of Follistim® AQ therapy, hCG should not be administered in this course of treatment; to reduce the chances of developing Ovarian Hyperstimulation Syndrome (OHSS). The Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a dramatic increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of OHSS developing are severe pelvic pain, nausea, vomiting, and weight gain. The following symptoms have been reported in cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see WARNINGS-Pulmonary and Vascular Complications). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS). During clinical trials with Follistim® therapy, OHSS occurred in 53 (5.2%) of the 1029 women treated and of these 29 (2.8%) were hospitalized. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and it can develop rapidly, reaching its maximum about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see PRECAUTIONS-Laboratory Tests), the hCG must be withheld. If serious OHSS occurs, treatment should be stopped and the patient should be hospitalized. Treatment is primarily symptomatic and should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Hemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity, and the pericardial cavity may occur and should be thoroughly assessed in the following manner: 1) fluid intake and output; 2) weight; 3) hematocrit; 4) serum and urinary electrolytes; 5) urine specific gravity; 6) BUN and creatinine; 7) total proteins with albumin: globulin ratio; 8) coagulation studies; 9) electrocardiogram to monitor for hyperkalemia and 10) abdominal girth. These determinations should be performed daily or more often based on clinical need. OHSS increases the risk of injury to the ovary. The ascitic, pleural, and pericardial fluid should not be removed unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should therefore be avoided. If bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible. Intercourse should be prohibited in patients with significant ovarian enlargement after ovulation because of the danger of hemoperitoneum resulting from ruptured ovarian cysts. The management of OHSS may be divided into three phases: an acute, a chronic, and a resolution phase. Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below. Acute Phase: Management during the acute phase should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Treatment is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Management includes administration of limited intravenous fluids, electrolytes, human serum albumin and strict monitoring of fluid intake and output. Monitoring for the development of hyperkalemia is recommended. Chronic Phase: After stabilizing the patient during the acute phase, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction. Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the return of the third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat pulmonary edema. Pulmonary and Vascular Complications Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported following gonadotropin therapy. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. Multiple Births Multiple births have been reported for all FSH treatments including Follistim® AQ (follitropin beta injection) treatment. The patient and her partner should be advised of the potential risk of multiple births before starting treatment. PRECAUTIONS General Careful attention should be given to the diagnosis of infertility and in the selection of candidates for Follistim® AQ (follitropin beta injection) therapy (see INDICATIONS AND USAGE-Selection of Patients). Information for Patients Prior to therapy with Follistim® AQ, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risks of Ovarian Hyperstimulation Syndrome and multiple births (see WARNINGS), and other possible adverse reactions (see ADVERSE REACTIONS) should be discussed.

Laboratory Tests In most instances, treatment with Follistim® AQ will result only in follicular growth and maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following the administration of Follistim® AQ or when clinical assessment of the patient indicates that sufficient follicular maturation has occurred. This may be directly estimated by sonographic visualization of the ovaries and endometrial lining and/or measuring serum estradiol levels. The combination of both ultrasonography and measurement of estradiol levels is useful for monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of OHSS and multiple gestations. The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows: a) A rise in basal body temperature, b) Increase in serum progesterone, and c) Menstruation following the shift in basal body temperature. When used in conjunction with indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following: a) Fluid in the cul-de-sac, b) Follicle showing marked decrease in size, and c) Collapsed follicle. Drug Interactions No drug-drug interaction studies have been performed. Carcinogenesis and Mutagenesis, Impairment of Fertility Long-term toxicity studies in animals have not been performed with Follistim® to evaluate the carcinogenic potential of the drug. Follistim® was not mutagenic in the Ames test using S. typhimurium and E. coli tester strains and did not produce chromosomal aberrations in an in vitro assay using human lymphocytes. Pregnancy Pregnancy Category X: (See CONTRAINDICATIONS). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Follistim® AQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of Follistim® did not include subjects aged 65 and over. ADVERSE REACTIONS Assisted Reproductive Technologies (ART) Rates of adverse events from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® in 989 infertile women treated with in vitro fertilization with Follistim® or urofollitropin after pituitary suppression with a GnRH agonist are summarized in Table 5. Table 5. Incidence of Adverse Clinical Experiences (>1%) Adverse Event Follistim® (n=591) Adverse Event Follistim® (n=591) Miscarriage 11.0% Abdominal pain 2.5% Ovarian Hyperstimulation Injection site pain 1.7% Syndrome 5.2% Vaginal hemorrhage 1.5% Ectopic pregnancy 3.0% Ovulation Induction Rates of adverse events from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® in 172 chronic anovulatory women who failed to ovulate and/or conceive during clomiphene citrate treatment are summarized in Table 6. Table 6. Incidence of Adverse Clinical Experiences (>1%) Adverse Event Miscarriage Ovarian Hyperstimulation Syndrome Abdominal discomfort

Follistim® (n=105) 9.5% 7.6% 2.9%

Adverse Event Abdominal pain, lower Abdominal pain Ovarian cyst

Follistim® (n=105) 2.9% 1.9% 2.9%

The following adverse events have been reported in women treated with gonadotropins: pulmonary and vascular complications (see WARNINGS), hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement), dizziness, tachycardia, dyspnea, tachypnea, febrile reactions, flu-like symptoms including fever, chills, musculoskeletal aches, joint pains, nausea, headache and malaise, breast tenderness, and dermatological symptoms (dry skin, erythema, body rash, hair loss, and hives). There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established. Congenital Anomalies The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no indications that the use of gonadotropins during ART is associated with an increased risk of congenital malformations. Storage Store refrigerated, 2–8°C (36–46°F) until dispensed. Upon dispensing, the product may be stored by the patient at 2–8°C (36–46°F) until the expiration date, or at or below 25°C (77°F) for 3 months or until expiration date, whichever occurs first. Protect from light, keep container in carton. Do not freeze.

For more detail regarding the information contained in this leaflet call 1-866-836-5633. www.follistim.com Follistim® is a registered trademark of N.V. Organon.

� only

Manufactured for Organon USA Inc. Roseland, NJ 07068 by Organon (Ireland) Ltd. Swords, Co. Dublin, Ireland FAQ-8007

1184 9/05 21

FOR SUBCUTANEOUS USE ONLY BRIEF SUMMARY Please see package insert for full prescribing information. INDICATIONS AND USAGE Follistim® AQ Cartridge (follitropin beta injection) is indicated for the development of multiple follicles in ovulatory patients participating in an Assisted Reproductive Technology (ART) program. Follistim® AQ Cartridge is also indicated for the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure. Selection of Patients Before treatment with Follistim® AQ Cartridge (follitropin beta injection) is initiated: 1) A thorough gynecologic and endocrinologic evaluation of the patient must be performed. The evaluation should include a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of reviewing a patient’s history, performing a physical examination, determining serum hormonal levels as indicated, and optionally performing an endometrial biopsy. Patients with tubal pathology should receive Follistim ® AQ Cartridge only if enrolled in an ART program. 2) Primary ovarian failure should be excluded by the determination of circulating gonadotropin levels. 3) Careful examination should be made to rule out early pregnancy. 4) Evaluation of the partner’s fertility potential should be included in the workup procedure. CONTRAINDICATIONS Follistim® AQ Cartridge (follitropin beta injection) is contraindicated in women who exhibit: 1) Prior hypersensitivity to recombinant hFSH products 2) A high circulating FSH level indicating primary ovarian failure 3) Uncontrolled thyroid or adrenal dysfunction 4) Tumor of the ovary, breast, uterus, hypothalamus, or pituitary gland 5) Pregnancy 6) Heavy or irregular vaginal bleeding of undetermined origin 7) Ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS) 8) Hypersensitivity reactions to streptomycin or neomycin. Follistim® AQ Cartridge may contain traces of these antibiotics and may cause hypersensitivity reactions in susceptible persons. WARNINGS Follistim® AQ Cartridge (follitropin beta injection) should be used only by physicians who are experienced in infertility treatment. Changes in brand (manufacturer), type (recombinant, urinary, etc.), and/or method of administration (Follistim Pen®, conventional syringe, etc.) may result in the need to adjust the dose. Follistim ® AQ Cartridge administered with the Follistim Pen® contains a potent gonadotropic substance and delivers on average an 18% higher amount of follitropin beta as compared to lyophilized preparations administered by conventional syringe. Accordingly, a lower starting dose for gonadotropin stimulation and dose adjustments during gonadotropin stimulation should be considered for each woman treated with Follistim® AQ Cartridge (see DOSAGE AND ADMINISTRATION in the full prescribing information). Overstimulation of the Ovary During Treatment With Follistim® AQ Cartridge (follitropin beta injection) In order to minimize the hazards associated with the occasional abnormal ovarian enlargement that may occur with Follistim® AQ Cartridge therapy, the lowest effective dose should be used (see DOSAGE AND ADMINISTRATION in the full prescribing information). Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels can further minimize the risk of overstimulation. If the ovaries are abnormally enlarged on the last day of treatment with Follistim® AQ Cartridge, hCG should not be administered in this course of treatment, to reduce the chances of developing Ovarian Hyperstimulation Syndrome (OHSS). Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a dramatic increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of OHSS developing are severe pelvic pain, nausea, vomiting, and weight gain. The following symptoms have been reported in cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see WARNINGS-Pulmonary and Vascular Complications). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS). During clinical trials with Follistim® and Follistim® AQ Cartridge therapy, OHSS occurred in 60 (5.3%) of the 1132 women treated and of these 33 (2.9%) were hospitalized. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and it can develop rapidly, reaching its maximum about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see PRECAUTIONS-Laboratory Tests), the hCG must be withheld. If serious OHSS occurs, treatment should be stopped and the patient should be hospitalized. Treatment is primarily symptomatic and should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Hemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity, and the pericardial cavity may occur and should be thoroughly assessed in the following manner: 1) fluid intake and output; 2) weight; 3) hematocrit; 4) serum and urinary electrolytes; 5) urine specific gravity; 6) BUN and creatinine; 7) total proteins with albumin: globulin ratio; 8) coagulation studies; 9) electrocardiogram to monitor for hyperkalemia and 10) abdominal girth. These determinations should be performed daily or more often based on clinical need. OHSS increases the risk of injury to the ovary. The ascitic, pleural, and pericardial fluid should not be removed unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should, therefore, be avoided. If bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible. Intercourse should be prohibited in patients with significant ovarian enlargement after ovulation because of the danger of hemoperitoneum resulting from ruptured ovarian cysts. The management of OHSS may be divided into three phases: an acute, a chronic, and a resolution phase. Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below. Acute Phase: Management during the acute phase should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Treatment is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Management includes administration of limited intravenous fluids, electrolytes, human serum albumin, and strict monitoring of fluid intake and output. Monitoring for the development of hyperkalemia is recommended. Chronic Phase: After stabilizing the patient during the acute phase, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction. Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the return of the third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat pulmonary edema. Pulmonary and Vascular Complications Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported following gonadotropin therapy. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. Multiple Births Multiple births have been reported for all FSH treatments including Follistim® (follitropin beta for injection) treatment. The patient and her partner should be advised of the potential risk of multiple births before starting treatment. PRECAUTIONS General Careful attention should be given to the diagnosis of infertility and in the selection of candidates for treatment with Follistim® AQ Cartridge (follitropin beta injection) (see INDICATIONS AND USAGE-Selection of Patients). Information for Patients Physicians must instruct patients on the correct usage and dosing of Follistim® AQ Cartridge (follitropin beta injection) in conjunction with the Follistim Pen®.

Patients should read and follow all instructions in the Follistim Pen® Instructions for Use Manual/Treatment Diary prior to administration of Follistim® AQ Cartridge. Prior to treatment with Follistim® AQ Cartridge, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risks of Ovarian Hyperstimulation Syndrome and multiple births (see WARNINGS), and other possible adverse reactions (see ADVERSE REACTIONS) should be discussed. Laboratory Tests In most instances, treatment with Follistim® AQ Cartridge (follitropin beta injection) will result only in follicular growth and maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following the administration of Follistim® AQ Cartridge or when clinical assessment of the patient indicates that sufficient follicular maturation has occurred. This may be directly estimated by sonographic visualization of the ovaries and endometrial lining and/or measuring serum estradiol levels. The combination of both ultrasonography and measurement of estradiol levels is useful for monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of OHSS and multiple gestations. The clinical evaluation of estrogenic activity (changes in vaginal cytology, changes in appearance and volume of cervical mucus, spinnbarkeit, and ferning of the cervical mucus) provides an indirect estimate of the estrogenic effect upon the target organs, and therefore, it should only be used adjunctively with more direct estimates of follicular development (e.g., ultrasonography and serum estradiol determinations). The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows: a) A rise in basal body temperature b) Increase in serum progesterone c) Menstruation following the shift in basal body temperature When used in conjunction with indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following: a) Fluid in the cul-de-sac b) Follicle showing marked decrease in size c) Collapsed follicle Drug Interactions No drug-drug interaction studies have been performed. Carcinogenesis and Mutagenesis, Impairment of Fertility Long-term toxicity studies in animals have not been performed with Follistim® AQ Cartridge (follitropin beta injection) to evaluate the carcinogenic potential of the drug. Follistim® (follitropin beta for injection) was not mutagenic in the Ames test using S. typhimurium and E. coli tester strains and did not produce chromosomal aberrations in an in vitro assay using human lymphocytes. Pregnancy Pregnancy Category X: (See CONTRAINDICATIONS). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Follistim® AQ Cartridge (follitropin beta injection), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies did not include subjects aged 65 and over. ADVERSE REACTIONS Assisted Reproductive Technologies (ART) Rates of adverse events from an open-label, non-controlled, multicenter study in 60 women undergoing COH for IVF or ICSI with Follistim® AQ Cartridge (follitropin beta injection) administered with the Follistim Pen® are summarized in Table 4. TABLE 4: Incidence of Adverse Clinical Experiences (≥5%) Adverse Event Abdominal pain Flatulence Abdominal pain, gynecological Nausea Breast pain, female Injection site reaction

Follistim® AQ Cartridge n=60 28% 27% 25% 17% 15% 10%

Adverse Event Abdomen enlarged Back pain Constipation Headache Ovarian pain

Follistim® AQ Cartridge n=60 8% 7% 5% 5% 5%

Ovulation Induction Rates of adverse events from an open-label, non-controlled, multicenter study in 43 clomiphene-resistant women with chronic anovulation (WHO group II) undergoing Ovulation Induction with Follistim® AQ Cartridge (follitropin beta injection) administered with the Follistim Pen® are summarized in Table 5. TABLE 5: Incidence of Adverse Clinical Experiences (≥5%) Adverse Event

Ovarian hyperstimulation syndrome Abdominal pain Injection site reaction

Follistim® AQ Cartridge n=43 9% 5% 5%

Adverse Event Sinusitis Upper respiratory tract infection

Follistim® AQ Cartridge n=43 5% 5%

The following adverse events have been reported in women treated with gonadotropins: pulmonary and vascular complications (see WARNINGS), hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement), dizziness, tachycardia, dyspnea, tachypnea, febrile reactions, flu-like symptoms including fever, chills, musculoskeletal aches, joint pains, nausea, headache and malaise, breast tenderness, and dermatological symptoms (dry skin, erythema, body rash, hair loss and hives). There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established. Congenital Anomalies The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no indications that the use of gonadotropins during ART is associated with an increased risk of congenital malformations. Storage Store refrigerated, 2–8°C (36–46°F) until dispensed. Upon dispensing, the product may be stored by the patient at 2–8°C (36–46°F) until the expiration date, or at 25°C (77°F) for 3 months or until expiration date, whichever occurs first. Once the rubber inlay of the Follistim® AQ Cartridge has been pierced by a needle, the product can only be stored for a maximum of 28 days at 2–25°C (36–77°F). Protect from light. Do not freeze. For more information, call 1-866-836-5633

Follistim® and Follistim Pen® are registered trademarks of N.V. Organon

� only

Manufactured for Organon USA Inc. Roseland, NJ 07068 by Vetter Pharma-Fertigung GmbH & Co. KG Ravensburg, Germany and packaged by Organon (Ireland) Ltd., Swords Co. Dublin, Ireland ©2005 Organon USA Inc.

FOP-8009

5310202-03 3/05 24

It all starts with

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Pre-mixed ready to use rFSH solution.1,2 1

Multiple dose 300, 600 and 900 IU Cartridges

Accurate fine-tuned dosing in 25 IU increments. 3

Micro volume (0.09 mL = 75 IU)

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No potential for urinary protein contamination4,5

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No risk of urine-based bacterial or viral contamination.4,5

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Store refrigerated or at room temperature for three months or until expiration date, whichever 1,2 occurs first.

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Single-dose 75 and 150 IU Vials (0.5 mL)

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SC administration.

IM administration. > 99% purity4,5

Batch-to-batch consistency

For more information, call 1-866-836-5633 or visit www.follistim.com For support visit www.fertilityjourney.com Please see accompanying Brief Summary

SAFETY INFORMATION on Follistim® AQ Cartridge and Follistim® AQ Vial • Follistim® AQ Cartridge/Vial, like all gonadotropins, is a potent substance capable of causing mild to severe side effects including OHSS, with or without pulmonary or vascular complications. • Follistim® AQ Cartridge/Vial, should be prescribed only by physicians who are experienced in infertility treatment and should advise their patients of treatment risks, including OHSS and multiple births. SAFETY INFORMATION on Follistim® AQ Cartridge • Follistim® AQ Cartridge administered with Follistim Pen® delivers on average an 18% higher amount of follitropin beta compared to lyophilized preparations administered with a conventional syringe and needle. A lower dose should be considered when using Follistim® AQ Cartridge. References: 1. Follistim® AQ (follitropin beta injection) Cartridge full Prescribing Information. Roseland, NJ: Organon USA Inc; 2005 2. Follistim® AQ (follitropin beta injection) Vial full Prescribing Information. Roseland, NJ: Organon USA Inc; 2005. 3. Craenmehr E, Bontje PM, Hoomans E, Voortman G, Mannaerts BMJL. Follitropin-ß administered by pen device has superior local tolerance compared with follitropin-α administered by conventional syringe. Reproductive BioMedicine Online. 2001;3:185-189. 4. Shoham Z, Insler V. Recombinant technique and gonadotropins production: new era in reproductive medicine. Fert. Steril: 1996;66:187-201. 5. van de Weijer B, Mulders J WM, Bos E S, Verhaert P DEM, van den Hooven H. Compositional analysis of a human menopausal gonadotrophin preparation extracted from urine(menotropin):identification of some of its major impurities.RBM Online, 2003; Vol. 7 no. 5 547-557.

Printed in the USA

August 2006

FER-1020