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“It’s not what you don’t know that makes you look like a fool. It’s what you do know that ain’t so.” - Appalachian Mountain Proverb Joseph A. Hill, M.D. Reproductive Medicine, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts There is no serious alternative to level one evidence derived from properly designed and implemented large-scale clinical trials. Unfor- tunately, few of these studies exist in the field of women’s reproductive medicine. The matter is further complicated by the entrepreneurial, almost carnival-like atmosphere that has en- veloped reproduction. Couples desperate for children are bombarded by a multitude of “in- fomercials.” No longer confined to painted wagons, modern-day “Professor Marvels” ped- dle their wares colorfully on the World Wide Web. For better or worse, patients’ use of the Internet can no longer be ignored. Novel tests and therapies concerning immunological theo- ries are promulgated; yet aside from subfertil- ity associated with antisperm antibodies, there remain no definitive data to date delineating the immunopathophysiology purportedly involved in infertility. Despite the absence of definitive data, the vociferous persistence of a few self-selected proponents of immunological testing for infer- tility speaks to powerful emotional needs of couples seeking reproductive care. Women with diminishing ovarian reserve and couples who have been through failed IVF cycles have difficulty comprehending that the most likely reason for not conceiving was due to chromo- somal anomalies in their oocytes. The thera- peutic option involving donor oocytes is often difficult for these infertile couples; rather, it is much easier for them to adopt the mentality that, “It is not a problem if they can throw money at it,” thus, rendering themselves sus- ceptible to the marketing efforts of those sell- ing tests and therapies of little, if any, clinical relevance. Separating wishful dreams from proven realities is often difficult. Sir Peter Me- dawar, Nobel laureate and founding father of Reproductive Immunology once said, “The in- tensity of the conviction that a hypothesis is true has no bearing on whether it is true or not.” Diagnostic testing requires knowledge of the test’s reproducibility, sensitivity, specific- ity, and positive and negative predictive values. As Professor Rodney Nichols (NY Acad Sci, 1997) said, “Testing and quality control is what has earned for science its special claim to knowledge.” The acknowledgment by the American Society for Reproductive Immu- nology (ASIR) Antiphospholipid Antibody Committee that because of the special nuances inherent in antiphospholipid antibody testing these tests can only be performed properly in certain laboratories is a serious drawback and is a concern for their clinical applicability. Lack of control standards increases the like- lihood that a positive test result will be ob- tained by pure chance. There are approximately 20 individual antiphospholipid antibody tests marketed that lack control standards. If the 95th percentile is used as a positive value, as is common practice, the probability of having at least one test return positive by chance alone is 64%. Antibodies to the phospholipid cardiolipin and the lupus anticoagulant may be responsible for recurrent pregnancy loss in a small number of women with what is known as the antiphos- pholipid syndrome. It is important that women with this syndrome do not experience difficulty conceiving but rather have difficulty carrying their pregnancies successfully to term. Thus, the statement by the ASIR Antiphospholipid Antibody Committee, “Immunologic factors Received and accepted May 22, 2000. Reprint requests: Joseph A. Hill, M.D., Reproductive Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115 (FAX: 617-566-7752; E-mail: [email protected]). FERTILITY AND STERILITYt VOL. 74, NO. 4, OCTOBER 2000 Copyright ©2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. 0015-0282/00/$20.00 PII S0015-0282(00)01531-4 637

“it’s not what you don’t know that makes you look like a fool. it’s what you do know that ain’t so.” - Appalachian Mountain Proverb

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“It’s not what you don’t know that makesyou look like a fool. It’s what you do knowthat ain’t so.” - Appalachian Mountain Proverb

Joseph A. Hill, M.D.

Reproductive Medicine, Department of Obstetrics, Gynecology, and Reproductive Biology,Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

There is no serious alternative to level oneevidence derived from properly designed andimplemented large-scale clinical trials. Unfor-tunately, few of these studies exist in the fieldof women’s reproductive medicine. The matteris further complicated by the entrepreneurial,almost carnival-like atmosphere that has en-veloped reproduction. Couples desperate forchildren are bombarded by a multitude of “in-fomercials.” No longer confined to paintedwagons, modern-day “Professor Marvels” ped-dle their wares colorfully on the World WideWeb. For better or worse, patients’ use of theInternet can no longer be ignored. Novel testsand therapies concerning immunological theo-ries are promulgated; yet aside from subfertil-ity associated with antisperm antibodies, thereremain no definitive data to date delineating theimmunopathophysiology purportedly involvedin infertility.

Despite the absence of definitive data, thevociferous persistence of a few self-selectedproponents of immunological testing for infer-tility speaks to powerful emotional needs ofcouples seeking reproductive care. Womenwith diminishing ovarian reserve and coupleswho have been through failed IVF cycles havedifficulty comprehending that the most likelyreason for not conceiving was due to chromo-somal anomalies in their oocytes. The thera-peutic option involving donor oocytes is oftendifficult for these infertile couples; rather, it ismuch easier for them to adopt the mentalitythat, “It is not a problem if they can throwmoney at it,” thus, rendering themselves sus-ceptible to the marketing efforts of those sell-ing tests and therapies of little, if any, clinicalrelevance. Separating wishful dreams from

proven realities is often difficult. Sir Peter Me-dawar, Nobel laureate and founding father ofReproductive Immunology once said, “The in-tensity of the conviction that a hypothesis istrue has no bearing on whether it is true or not.”

Diagnostic testing requires knowledge ofthe test’s reproducibility, sensitivity, specific-ity, and positive and negative predictive values.As Professor Rodney Nichols (NY Acad Sci,1997) said, “Testing and quality control iswhat has earned for science its special claimto knowledge.” The acknowledgment by theAmerican Society for Reproductive Immu-nology (ASIR) Antiphospholipid AntibodyCommittee that because of the special nuancesinherent in antiphospholipid antibody testingthese tests can only be performed properly incertain laboratories is a serious drawback andis a concern for their clinical applicability.Lack of control standards increases the like-lihood that a positive test result will be ob-tained by pure chance. There are approximately20 individual antiphospholipid antibody testsmarketed that lack control standards. If the95th percentile is used as a positive value, asis common practice, the probability of havingat least one test return positive by chancealone is 64%.

Antibodies to the phospholipid cardiolipinand the lupus anticoagulant may be responsiblefor recurrent pregnancy loss in a small numberof women with what is known as the antiphos-pholipid syndrome. It is important that womenwith this syndrome do not experience difficultyconceiving but rather have difficulty carryingtheir pregnancies successfully to term. Thus,the statement by the ASIR AntiphospholipidAntibody Committee, “Immunologic factors

Received and acceptedMay 22, 2000.Reprint requests: JosephA. Hill, M.D., ReproductiveMedicine, Brigham andWomen’s Hospital, 75Francis Street, Boston,Massachusetts 02115(FAX: 617-566-7752;E-mail: [email protected]).

FERTILITY AND STERILITY tVOL. 74, NO. 4, OCTOBER 2000Copyright ©2000 American Society for Reproductive MedicinePublished by Elsevier Science Inc.Printed on acid-free paper in U.S.A.

0015-0282/00/$20.00PII S0015-0282(00)01531-4

637

by and large affect implantation which is mainly a femalerelated event,” is peremptory. Based on what direct immu-nopathological evidence do they make this claim? This com-mittee did not acknowledge that women with high-titer auto-antibodies due to autoimmune diseases, such as systemiclupus erythematosus, do not have difficulty with implanta-tion; rather, these women, again, have difficulty in carryingtheir pregnancies to viable term delivery. There is no proofthat antiphospholipid antibodies cause infertility, which iswhy The American Society for Reproductive Medicine(ASRM) Clinical Practice Committee was compelled towrite their cogent report against antiphospholipid antibodytesting in IVF. However, as Julius Caesar observed, “Peoplewillingly believe what they will.”

The ASIR’s Antiphospholipid Antibody Committee alsosuggested that immunological treatments for infertility areclinically justified because other therapies used to treat in-fertility have not been adequately tested. This line of rea-soning palls, risking the addition of still more unsubstanti-ated therapies to an already cumbrous therapeutic repertoireresulting in further burgeoning of health care expendituresand the potential exploitation of infertile couples seekingcare.

The ASIR’s Antiphospholipid Antibody Committee alsotook exception to the selection of journal articles analyzedby the ASRM Clinical Practice Committee. The reasonsthose articles were chosen and their statistical methods usedwere well defended in the ASRM Clinical Practice Commit-tee report and are further reemphasized by Dr. Mark Horn-stein’s response to Dr. Coulam and her committee’s com-mentary and so will not be further discussed here. However,the quality of published reports has been the subject of manyeditorials over the years.

The lay public and many physicians alike often havedifficulty assessing the quality of published reports. Manysee all publications similarly and believe that if it is pub-lished, it certainly must be clinically relevant, or it would nothave been published. The rather satirical editorial publishedin JAMA (1986;256:2391) addressed this issue: “Thereseems to be no study too fragmented, no hypothesis tootrivial, no literature citation too biased or too egotistical, nodesign too unwrapped, no methodology too bungled, nopresentation of results too inaccurate, too obscure, and too

contradictory, no analysis too self-serving, no argumenttoo circular, no conclusions too trifling or too unjustified,and no grammar and syntax too offensive for a paper to endup in print.”

Who then is responsible for quality studies? The burdenclearly falls first and foremost on the investigators, who,poised with a hypothesis to test, should seek collaborationswith those knowledgeable in quality study design and im-plementation. Reviewers and editors are also responsible, foras an editorial inThe Lancetmade clear, “The proportion oftrials published by a journal that have invalid designs isa measure of the journal’s quality.” Lastly, readers them-selves are responsible. But, alas, as Professor Carl Sagansaid, “We live in a gullible society where hope not skepti-cism sells.” According to Bertrand Russel, “What is neededis not the will to believe, but the wish to find out, which isthe exact opposite.”

Arnold S. Relman, M.D., writing inPharos(1978;1:18–22) concerning controversy in medicine, stated that “Theethical duty of every physician is to be sure that the tests andprocedures he or she uses are worth the money, inconve-nience and risks involved.” The ASRM Clinical PracticeCommittee made clear the reasons why antiphospholipidantibody assessment in women with infertility did not makeclinical sense. It should be conceded, however, that assess-ment of these autoantibodies does generate clinical dollarsfor those performing these tests. Remuneration interestsaside, one can agree with Dr. Coulam and her committee thatit is indeed “in the best interest of all that reproductiveimmunology research be encouraged.” However, we owe itto ourselves, and most importantly to our patients, to per-form these studies in scientifically cogent, well-designed,hypothesis-driven, clinical trials. Furthermore, the costs ofinvestigative tests and therapies should be borne either bythe investigators themselves or by funding agencies and notat the financial expense of either couples seeking care ortheir third-party payers. Dr. Coulam and her committeeshould be encouraged to perform such studies.

Level one evidence derived from appropriately designedand implemented clinical trials should empower us to leavebehind the dogmas of the old, “For this do that mentality,”enabling a “Renaissance” in both the art and the science ofreproductive medicine.

638 Hill It’s not what you don’t know Vol. 74, No. 4, October 2000