Challenges of risk and safety management（RSM）in infertility and ART：A proactive recipe

2014-05-12DominiquedeZieglerPietroSantulliIsabelleStreuliRebeccaMonfatAnnaRaggiAlexandraAmbrosettiPaulPirteaCharlesChapron

生殖医学杂志 2014年3期

关键词：错误医疗

Dominique de Ziegler，Pietro Santulli ，Isabelle Streuli ，Rebecca Monfat，Anna Raggi ，Alexandra Ambrosetti ，Paul Pirtea，Charles Chapron

1．UniversitéParis Descartes，Paris Sorbonne Cité-Assistance Publique Hǒpitaux dep aris，CHU Cochin，Department of Obstetrics ＆Gynecology，Division of Reproductive Medicine，Paris，France．

2．Department of Obstetrics ＆ Gynecology，Division of Reproductive Medicine，Hopitaux Universitaires de Genève，Genève，Switzerland．

3．Department of Biomedicine，Research Group on Gynecological Endocrinology，University Hospital，University of Basel，Basel，Switzerland．

Safety in medicine：Infertility and ART as test bench

Medicine and aviation share in common the fact that both gone industries have gone through ground-shaking technological changes，as each has incorporated some of the most spectacular and ground-shaking man-made achievement of modern times．Yet in this process，medicine and aviation differ on at least one point，their respective safety records，a difference that is not in the honor of medicine．Indeed，whereas aviation has followed an improbable path that took it to become the safest mode of transportation on earth，medicine has most dreadfully lagged behind when it comes to safety records．The remarkable accomplishments made by aviation in the field of safety did not happen by chance，but on the contrary resulted from an active design and relentless efforts that for years has put safety first．Public concerns for airline safety，pro-active intelligent will，industry-sensitive and reactive government regulations，as well as the fact that the pilots’lives are at stake each played an important role in today’s levels of safety achieved by aviation．

Medicine however suffered from lesser levels of concern and lack of similar universal standards and reactive unified and intelligent regulations，as compared to aviation．Awareness is now rising however，with an increasing number of seminal publications．Notably，the Institute of Medicine（IOM）documenting how unsafe medical practice is and outlining steps that must be taken to improve safety outcomes．In the field of infertility and assisted reproductive technologies（ART）alone，five dedicated articles on risk and safety management were recently published as part of a coordinated series［1－3］．

In a newly launched pursuit for safer medicine，infertility and ART stands in the position of possibly playing a unique and particularly important role for the following reasons：

1．Women needing infertility and ART are generally healthy，yet are exposed to serious medical risks．For male factor infertility，the woman assuming those risks likely suffers no problems of her own．

2．Due to lasting exposure to the news media and legislative scrutiny，ART was one of the first domains of medicine to be confronted to high-level regulations and controls．Infertility and ART has been exposed for example，to mandatory training requirements，laboratory accreditation，and guidelines for patient care．

3．Because of results still hover between 0%and 100%-despite improvements-and sometimes misleading use of intermediate outcomes （e．g．，clinical pregnancy rather than delivery rates），ART has been required to report its results to government agencies in a standardized fashion．Only several other medical activities are required to report such detailed treatment outcomes．

4．A variety of quality control processes are often mandated because outcomes can be significantly affected by minute environmental and procedural factors．

Rather than seeing the regulatory obligations that befell on infertility and ART solely as burden，one should consider on the contrary that ART might constitute an ideal field of medicine for further development and implementation of a global risk and safety management（RSM）program．

Hazards and risks

Prefatory to addressing the pertinent recipes for improving the practical efficacy of RSM in in-fertility and ART，it is important to define two closely related yet different concepts，hazard and risk．Hazards，are defined as‘intrinsic and‘potential sources of danger’．This therefore refers to the immutable conditions of a given activity or situation．For example，in mountain climbing the hazard stems from height，a characteristic inherent to the fact that mountains are what they are．By nature therefore，hazards cannot be changed．Risks，however，refer to ‘the possibility that something unpleasant or unwelcome could happen’．In our mountain climbing example，the concept of risk describes the possibility that a slip occurs and causes a fall of possibly dreadful consequences．

Practically therefore，the hazards that are inherently linked to a given activity－possible vascular and bacteriological breaches in case of surgery，as a result of introduction instruments in the bodyhave to identified．The consequences of known risks that may exist in relation with such hazardsi．e．hemorrhage and／or infection-must be fully reviewed in order to proactively prevent their occurrence by enacting proper defense mechanisms and／or countermeasures．

Practically，defense mechanisms in medicine consist of procedures aimed at minimizing the probability that errors-analyzed in the context of the prevailing risks and hazards-will result in patient harm［8］．These efforts at prevention of harm to patients and providers that might result as consequences of hazards and risks are the essence and primary goals of RSM．

Clinical risks in ART

The consequences of clinical risks-known as adverse events（AEs）-encountered while managing infertility and dispensing ART protocols are generally of three types：（i）Certain AEs stem from the generic risks commonly associated with all invasive procedures（hemorrhage and infections）；（ii）Other AEs are associated with the so-called controlled ovarian stimulation（COS）treatment used in ART for assuring the multiple harvests known to enhance pregnancy chances and：（iii）a remaining category of AEs are simply associated with personal characteristics of certain individuals undergoing ART．

AEs associated with all invasive procedures

Hemorrhage and Damage to Adjacent Organs

Hemorrhage is encountered in＜1%of ART cases，with bleeding occurring intra or extra-peritoneally．The former causes abdominal pain and distension，typically 2-6hours after the retrieval，with abundant intra peritoneal blood seen on ultrasound examination．Retroperitoneal bleeding generates prompter and more severe symptoms．In the latter case，ultrasounds show normal amounts of fluid and often an area of retroperitoneal distension with blurred limits and exquisite tenderness．Unless spontaneous resolution is witnessed，both forms of bleeding are commonly cured surgically．

Likewise，damage to the bowel，bladder and ureter may occur during the oocyte retrievals．Serious consequences can follow if early symptoms are ignored．

Infection

The risk of infection after oocyte retrievals is real and higher when endometriomas are present［4］．Direct complications of tubo-ovarian abscesses may even include caused consumption coagulopathy［5］．Clinical symptoms are classically extremely variable，usually occurring a few days after the retrieval，but sometimes with late onset（weeks or months，including during pregnancy）［6］．Surgical exploration and at times adnexectomy may be needed［7］．Generally utmost efforts must be deployed for not entering these cysts during retrieval if at all possible［8］．

AEs Unique to ART

Examples of AEs that are due directly to treatments unique to ART include ovarian hyperstimulation syndrome（OHSS），multiple pregnancies and disorders of placentation．

Ovarian Hyperstimulation Syndrome（OHSS）

While the risk of OHSS has greatly decreased with antagonist protocols，its discussion is appropriate because OHSS has for so long been the emblematic complication of ART，sometimes with dreadful complications．Anticipating COS responses based on age，body weight，menstrual cycle irregularity and hormonal profile leads to treatment adjustments．Yet in spite of tailoring COS regimens，excessive responses resulting in OHSS may still occur．

During COS，when the risk of OHSS is imminent，further development toward more serious stages can be stopped or controlled by series of possible measures．These notably include：withholding human chorionic gonadotropin（hCG）injection，‘coasting’without administrating any medication or deferring embryo transfer（Dif-ET）to a subsequent cycle．If OHSS nonetheless occurs，modern treatment（i．e．water and electrolyte management，repetitive paracentesis，intravenous albumin，prophylactic heparin，etc．）effectively averts the dreadful and possibly fatal consequences of thromboembolism or organ failure that might otherwise occur．Significant AEs most often result from poor management of OHSS，rather than OHSS itself［9］，making the promotion of proper management of OHSS the single most effective measure for curbing the dreadful consequences of this complication of ART treatments．

Multiple Pregnancies

Today，systematically transferring 2embryos carries a twin pregnancy rate of 30%-50%，while systematic single embryo transfers lower pregnancy success．Opting for elective single embryo transfer（eSET）when all parameters are highly favorable minimizes twin pregnancy rates，with a minor impact on the odds of pregnancy being achieved．Recently，trophectoderm biopsies performed at the blastocyst stage associated with comprehensive chromosome screening（CSS）allows to systematically transferring single euploid blastocysts with pregnancy rates equaling those achieved with dual unscreened blastocyst transfers［10］．

Placentation Disorders

Recently，converging reports have concurred to describe an increase in the incidence of certain obstetric complications in ART．These include notably，（e．g．，preeclampsia，bleeding episodes，small for）in singleton ART pregnancies．While the respective roles of ART and infertility are difficult to establish，a lower incidence of these problems is encountered following frozen embryo transfers（FET）［11］．

Indeed，most if not all of the obstetric problems encountered after ART may stem from disordered placentation due to endometrial abnormalities seen in COS，but not with FETs．Finding larger placentas and higher placental weight／birthweight ratios in ART as compared to spontaneous pregnancies supports this concept［11］．

AEs favored by Personal Risk Factors

The third category of AEs encountered in ART encompasses those that are due to the unique risks or predispositions that an individual woman undergoing ART may have．Examples of AEs due to personal risks include adverse vascular events，cytogenetic abnormalities leading to AEs and uterine defects that may lead to AEs．

Vascular AEs（venous）

Certain patients may be predisposed to vascular thrombosis-embolism （VTE）events．These individuals，typically identified by apersonal and／or family history of VTE，require heparin prophylaxis during ART．While routine checking of hemostasis-related mutations is not warranted，recognizing that OHSS induces a 100-fold increase in VTE risk is crucial．However，no increased risk is seen with FETs，further fueling the interest in deferring embryo transfers．

Failure to identify women at particular risk for VTE upfront could be fatal，because unlike OHSS there are usually no obvious clinical signs prior to a VTE adverse event．Protective barriers must concentrate on not failing to identify individuals at risk who may need heparin prophylaxis during ART．Considering the seriousness of the issue，we suggest that all ART candidates should be asked the same question using the exact same terms：“have you personally had a blood clot，or were there people in your family who died under age 50of a heart attack or without any apparent reason？”While not aguarantee，a negative answer may be more reliable when a standardized question is used．

The risks from each of these conditions（OHSS and VTE）have different dynamics．Each risk therefore needs different protective defenses to effectively prevent their respective AEs．

Cytogenetic AEs

Chromosomal and genetic risks leading to AEs are personal conditions bearing possible threats for 1）the child，e．g．，fragile-X pre-mutation leading to fragile-X mental retardation in a male offspring，or 2）the patient，e．g．，Turner syndrome，possibly exposing the patient to fatal rupture of the aorta during pregnancy，an SE．

AEs due to Uterine Malformations

Risks due to uterine malformations，such as fibroids or prior scars can put the pregnancy at a higher risk for obstetric complications，sometimes dictating eSET or surrogacy to avoid the risks．As with other personal risks，identification

From aviation to medicine

AS recently reviewed in sets of articles in a lead journal in the field［1－3］，it has become commonplace to praise the aviation-inspired measures aimed at enhancing safety．This notably includes the famous checklists that pilots are known go through prior to undertaking any of the crucial steps of flights．Such safety-minded measures inspired from aviation have been already enacted in medicine，including checklists， pre-procedural briefings and medical teamwork［12］．In many but far from all operating rooms（OR）and intensive care units，these tools have been adopted and have been highly successful at eliminating the mega mistakes-eg．the“triple W”consisting of operating on the wrong patient，wrong side and wrong organwhere they have been implemented．In the OR，a simple preoperative checklist reduced surgical mor-tality by 47%worldwide at study institutions［13］．

The aviation-inspired safety measures that have proven to be so highly effective in the OR have not entered the doctor’s office however．Hence，the measures described above did little to dent the more fundamental errors of medicine such as making the wrong diagnosis or wrong surgical indication that still constitute a significant problem and remains the cause of lots of unnecessary harm．In 2008，the American College of Obstetricians and Gynecologists（ACOG）established a task force to study and make recommendations for the implementation of safety tools and procedures in the outpatient setting．This initial effort led in part to the development of ACOGs more comprehensive Safety Certification in Outpatient Practice Excellence（SCOPE）program．The RSM process discussed here aims at addressing risk and safety issues in the sub-specialty of infertility，inclusive of the doctor’s office where procedures involving risks are initiated and often performed．In that，RSM is to be seen as a complement and not a competing system to existing quality systems such as the International Organization for Standardization certification programs［7］and other certification processes that already exist in ART．For the reasons outlined above，we believe that infertility and ART may constitute an ideal field of medicine for further development and implementation of a global risk and safety management（RSM）program．

Medical education with‘safety inside’

Academic and professional training

A lasting confusion has existed in medicine between academic education and professional training．Medicine in general involves highly complex and scientifically rooted processes that imply a full understanding of cutting-edge biological sciences and mastering an array of high-tech innovations in medicine．These notably include what has become today’s by-excellence field of scientific achievements，medical genetics．Proficiency for navigating through the meanders of all the technical novelties is in essence the domain of and the justification for academic education that is offered through years of medical school．

Conversely，professional education-the mastering of the medical specialty or sub-specialty-has needs for structured and controlled training，which must to be dispensed with asafety-insidephilosophy．The latter needs are largely unmet to date．Certain supervising boards and education councilsi．e．the American Board of Obstetrics and Gynecology and others in Europe，Australia and Canada-have defined the perimeter of the educational needs（or，the training curriculum）that must accompany the hands-on orfellowship-typetraining in infertility and ART．But，the practical supervision that the appropriate training is provided is still primarily resting on solely，or mainly，testing the candidate．A more effective way of controlling the quality of professional training would consist in instituting more stringent supervising schemes overseeing the trainers．Such controls would assure that proper means are deployed for effectively covering the whole educational curriculum during the fellowship program so as to fulfill the requirements defined by the regulatory board or council．In cases where part or all of the educational curriculum can not be provided in house（lack of sufficient personal），it would be perfectly acceptable that such training is subcontracted to another teaching institution．

An example of ad hoc education support of fellowship-type training is illustrated in Fig．1．In this model，the educational support in infertility and ART is given in the form of two 1-week courses（initial and validation）and 9advanced education modules given throughout the fellowship training．The 9advanced educational modules address the following topics．

The nine three-day advanced education modules will cover the following topics：

★ Module＃1

Physiology of ovulation and pathophysiology of ovulatory dysfunctions．Ovulation，oligo-anovulation，induction of ovulation，controlled ovarian stimulation（COS），luteal phase support（LPS）．

★ Module＃2

Surgery and infertility：Endometriosis，ovarian cyst，fibroids，uterine and tubal malformations．Define the role played by the exploratory laparoscopy in the infertility work up．

★ Module＃3

Ovarian function and dysfunction and aging．Concept of ovarian reserve，menopause and premature menopause

★ Module＃4

Epidemiology of fertility and infertility and secular trends．Inter-racial and ethnical differences．

★ Module＃5

Embryology，reproductive histology of infertility and ART

Genetics（I），trophectoderm biopsies for preimplantation genetic screening（PGS）and embryo／oocyte quality assessment．

★ Module＃6

Risk and safety management（RSM）in infertility and ART．Define hazards and risks．Principles of error and error management．

Fundamentals ofevolutiveknowledge．Basic knowledge in clinical research．Conception of protocols，practical implementation，data analysis and reporting（oral and written）．Fundamentals of critical reading．

★ Module＃7

Body-mind harmony，fertility and reproduction．Psycho and psychosocial issues．

★ Module＃8

Genetics（II），screening for embryo anomalies and fetal malformation．Pre-implantation genetic diagnosis（PGD）．

★ Modules＃9

Fundamentals of‘medicalship’，a novel concept defined by analogy to seamanship and airmanship．Management，interpersonal relationship，interaction with outside institutions and professional societies．

A3D Central Education Unit（CEU）

Classically，the educational material used as support for professional as well as academic teach-ing is offered in book-type format in the form of syllabus or other type of documents．Departing from this traditional strategy，we developed a central education unit（CEU）serving for all the educational support offered as complement to the hands-on orfellowship-typetraining in infertility and ART．The primary originality of the CEU as compared to the classical book-type support lies in the fact that the CEU stores all the relevant educational materials in 3Dformat，using depth for grading materials of increasing complexity．As illustrated in Fig．2，three primary depth levels reflect the‘need-to-know’，‘nice-to-know’and ‘expert’levels of knowledge．

From‘airmanship’to the new concept or‘medicalship’

By analogy to the conceptseamanshipthat refers to the skills，techniques，or practice of handling a ship or boat at sea，people have created the word ofairmanshipfor describing a similarly global notion encompassing all the skills and knowhow involved in flying an aircraft．Airmanshipis further defined as covering the consistent use of good judgment and well-developed skills to accomplish flight Objectives．Airmanship therefore implies a high state of situational awareness encompassing the knowledge of one’s self，aircraft，environment，team and risk．In that，airmanshipis not simply a measure of skill or technique，but also a measure of a pilot’s awareness of the aircraft，the environment in which it operates，and of his own capabilities．Aside of defining the ability to operate an airplane with competence and precision both on the ground and in the air，airmanshipalso implies the exercise of sound judgment that results aimed at securing optimal operational safety and efficiency．

Considering the high degree of efficacy and safety that aviation has managed to secure，the operating systems that have been developed to that end and have been instrumental for achieving these goals deserved to be expanded to other territories such as notably，medicine．With this Objective in mind，we coined the word of‘medicalship’for en-compassing a similarly global concept of defining the skill and knowledge necessary for safely and efficiently perform as a physician．Medicalshipimplies accomplishing the tasks of caring for our patients’needs-in infertility，the couples’desires for a family-and if need be take them through and offer the most appropriate treatments．

Reporting errors

The reporting of errors，irrespective of whether harm occurs，is a key step in RSM．Making this a habit however needs to overcome traits of human nature that tend to avoid coming forward after errors are committed and／or a rule is violated．Each and every one of us seems hardwired to minimize errors and safety lapses that result in limited to no consequences．Neither an undue tolerance of errors，seemingly without consequences，or individual blame when an error leads to significant harm，do little to enhance safety．

On the contrary，errors cannot be ignored and should be dealt with．It has been clearly demonstrated in aviation that awareness of all errors is key to improving safety．Error awareness therefore implies initiating effective means of error reporting．Three primary modes of error reporting are recognized in aviation：1）automatic，2）mandatory and 3）voluntary．All three Methods need to applied to ART as well，but in ways that remain confidential-not anonymous-and non punitive．

Automatic Reporting

Automatic error reporting was instrumental in raising the safety level in aviation．The automatic nature of error reporting plays a crucial role，as it allows counteracting the human tendency for either ignoring or blaming，depending on outcome．In aviation，flight recorders are set for automatically reporting certain non-ordinary events occurring in flight such as for example，an excessively steep approach to landing．The first question asked generally is what happened？Sometimes good reasons for these errors exist．More often however，an excessively steep approaches results from sets of or-dinary blunders．The crucial initial step however is to know what exactly happened，so that an analysis can be conducted and that ultimately，individual or collective remediation take place．The information gained from investigations sparked by the automatic reporting of unusual event is confidentially shared with others in the industry so that all can learn from anyone’s mistakes．An important point is that all crewmembers-pilots and non-pilots-are exposed to a similar scrutiny，which sets the basis for a so-called‘just culture’．This ultimately nurtures a voluntary mode of error reporting and treating all errors regardless of outcome as events that need to be investigated［14］．

Automatic reporting-still rudimentary in infertility and ART-aims at changing people’s attitude about error analysis．In that，implementing different forms of automatic reporting aims at moving toward instituting and maintaining a‘fair and just culture’．

Mandatory Reporting

Certain events need to be reported and analyzed even if they are not necessarily due to errors．In ART，for example，each program should have mechanisms in place to review instances where no oocytes were retrieved or fertilization failed．These two events may not be due to medical error but rather to patient characteristics．However，when either of them occurs the clinical and laboratory processes should be reviewed．When patients undergo ART who are at higher risk（advanced age／poor responders and male factor）for these disappointing‘process outcomes’an expected result based on reported results elsewhere should be compared to the actual outcomes as a way of benchmarking the results．Benchmarking can be a powerful tool to compare results and evaluate performance，especially when error is not likely．

Disclosure of medical error to patients，including any unexpected adverse events，is or should be required by regulatory groups．A voluntary process for full disclosure to patients should be built into any RSM for infertility and ART．

Voluntary Reporting

Voluntary non-punitive reporting is a key to safety in medical operations．A culture favoring non-punitive reporting will allow earlier discovery of medical errors and AEs and permit actions，such as systems redesign when needed．In the U．S．，the Federal Aviation Agency（FAA）has enacted an‘Aviation Safety Action Program（ASAP）’that allows pilots（or controllers）to report an incident confidentially．Voluntary reporting，however，will not happen out of the blue in medicine．Strong leadership and incentives for voluntary reporting are needed．We personally believe that in medicine，voluntary reporting ought to be sealed in a protective domain that could not be used in court．The model that secludes the exchanges of information taking place between lawyers and clients could serve as constructive model．

The‘say what you do’approach to keep the Doctor in charge

Procedures Within Accepted Guidelines

A core issue in RSM is the necessity to have defined and standardized procedures that need to be applied and complied with．This is necessary for monitoring and detecting deviations．However，the art of drafting and following ad hoc procedures is inconsistent in clinical medicine，a fact that has been a stumbling block for implementing safety systems that go beyond the mere checklist and the like measures．

Some aspects of ART practice are getting entangled in ever-tighter meshes of‘top-down’rules and regulations that are expanding to the possible point of hindrance．Regulations are excessively complex，not up to date and impractical to implement．As in other industries，impractical and outdated measures are prone to pave the way for unlawful deviations and violations in order to simply keep the system working and maintain practice flow．Further expansion of rules and regulations，however noble the safety purpose，can add insult to injury to an already entangled system．Simply adding more rules and regulations is not，as we see it，the best way toward safer ART．

Rather than just making more rules，RSM needs to invent new modes of doctor-regulator interaction that promote safety and embed reliability into the culture of practice．

ART and Certification Systems

In many countries，the vulnerability and riskexposed nature of ART led the supervising authorities to recommend traditional quality assurance systems such as notably，certification according to the International Organization for Standardization（or ISO certification）［15］．

The certification documents such as the protocols and SOPs describing ART processes are starting points for RSM．They offer a“say what you do”approach upon which RSM can be built．Yet，risk management is not always an inherent part of quality and certification processes．RSM，with its own safety-minded agenda，will work with ISO but is not simply ISO．RSM and quality systems are like a computer program and its operating systemsthey work together，but each is different．

Conclusion

Although not bound to be that way when the Wright Brothers took off 110years ago in their makeshift airplane at Kitty Hawk，aviation has become today the safest mode of transportation on earth．This improbable achievement did not occur by chance，but rather resulted from relentless efforts from the side of the aircrews，operators and regulators．Today，medicine has much to learn from the realm of aviation if not necessarily from the sole airline segment of aviation．

Practical definition and implementation of RSM processes inspired from aviation and intelligently adapted to medicine can be instrumental in bringing medicine and its clinical operation to higher levels of safety than currently achieved．In this process，we believe that the medical domain of infertility and ART may serve as a unique test bench for proceeding through these changes．This is because ART is already under an uncommon degree of scrutiny from governmental agencies to which yearly reports of activity are requested．

Fig．1 Professional Education in infertility and ART

Fig．2 The central education unit（CEU）

［1］ Meldrum DR，de Ziegler D．Introduction：Risk and safety management in infertility and assisted reproductive technology［J］．Fertil Steril，2013，100：1497-1498．

［2］ de Ziegler D，Gambone JC，Meldrum DR，et al．Risk and safety management in infertility and assisted reproductive technology（ART）：from the doctor＇s office to the ART procedure［J］．Fertil Steril，2013，100：1509-1517．

［3］ Scott RT Jr，De Ziegler N．Could safety boards provide a valuable tool to enhance the safety of reproductive medicine？［J］．Fertil Steril，2013，100：1518-1523．

［4］ Benaglia L，Somigliana E，Iemmello R，et al．Endometrioma and oocyte retrieval-induced pelvic abscess：a clinical concern or an exceptional complication？［J］．Fertil Steril，2008，89：1263-1266．

［5］ Kelada E，Ghani R．Bilateral ovarian abscesses following transvaginal oocyte retrieval for IVF：a case report and review of iterature［J］．J Assist Reprod Genet，2007，24：143-145．

［6］ Moini A，Riazi K，Amid V，et al．Endometriosis may contribute to oocyte retrieval-induced pelvic inflammatory disease：report of eight cases［J］．J Assist Reprod Genet，2005，22：307-309．

［7］ Younis JS，Ezra Y，Laufer N，et al．Late manifestation of pelvic abscess following oocyte retrieval，for in vitro fertilization，in patients with severe endometriosis and ovarian endometriomata［J］．J Assist Reprod Genet，1997，14：343-346．

［8］ Tsai YC，Lin MY，Chen SH，et al．Vaginal disinfection with povidone iodine immediately before oocyte retrieval is effective in preventing pelvic abscess formation without compromising the outcome of IVF-ET［J］．J Assist Reprod Genet，2005，22：173-175．

［9］ Madill JJ， Mullen NB， Harrison BP ． Ovarian hyperstimulation syndrome：apotentially fatal complication of early pregnancy［J］．J Emerg Med，2008，35：283-286．

［10］ Forman EJ，Hong KH，Franasiak JM，et al．Obstetrical and neonatal outcomes from the BEST Trial：single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates［J］．Am J Obstet Gynecol，2014，210：157．e1-6．

［11］ Haavaldsen C，Tanbo T，Eskild A．Placental weight in singleton pregnancies with and without assisted reproductive technology：apopulation study of 536，567pregnancies［J］．Hum Reprod，2012，27：576-582．

［12］ Neily J，Mills PD，Young-Xu Y，et al．Association between implementation of a medical team training program and surgical mortality［J］．JAMA，2010，304：1693-1700．

［13］ Haynes AB，Weiser TG，Berry WR，et al．A surgical safety checklist to reduce morbidity and mortality in a global population［J］．N Engl J Med，2009，360：491-499．

［14］ Emanuel L，Berwick D，Conway J，et al．What exactly is patient safety？［A］In：Henriksen K，Battles JB，Keyes MA，Grady ML，eds．Advances in Patient Safety：New Directions and Alternative Approaches（Vol 1：Assessment）［M］．Rockville（MD），2008．［15］ Alper MM．Experience with ISO quality control in assisted reproductive technology［J］．Fertil Steril，2013，100：1503-1508．

【编者注：为方便读者阅读，附上齐格勒教授文章的中文译文】

一、医疗安全：不育和辅助生殖技术（ART）试点

医学和航空有许多相同点，两者都是经由重大技术突破带来更新与发展，都采用了众多当代最令人震撼的发明创造。然而，医学和航空至少有一点不同，那就是各自的安全记录，这也是医学为之汗颜的差别。航空业循着一条不可思议的道路前行，到如今变成了地球上最为安全的运输模式，而医学在安全性方面极大地落后于航空。航空业在安全领域的非凡成就并非出于偶然，而是缘于多年来安全至上理念的主动设计和不懈努力。公众对飞行器安全性的关注、积极主动的意愿、深具行业敏感性及行业反应性的政府管理条例、以及飞行员自身安全的利益攸关，都在当今良好的航空安全性上起着重要作用。

然而，相对于航空而言，医疗安全受到的公众关注程度较低，也缺乏类似的通用标准及统一的智能管理条例。不过，随着越来越多深具影响力的研究资料的发布，对于医疗安全的认识也在与日俱增。其中，最值得提出的是，美国医学研究所（I O M）汇文展示了医疗实践的不安全程度，并归纳出为改善安全结局所必须采取的行动步骤。单就不育和A R T而言，就有多个专于安全风险管理（R S M）的文章于近期发布［1－3］。

在新推出的“更安全的医疗”运动中，不育和ART处于一种绝无仅有的独特地位，理由如下：（1）需求ART治疗的不育妇女大体上是健康的，但置身于严重的医疗风险之中，而那些因男性因素不育的妇女自身可能毫无问题，但承担着这些医疗风险；（2）因为受到新闻媒体和立法审查等长期不懈的监督，ART成为首个遭遇高水平管理和监控的医疗领域。例如，不育治疗和ART一直需要遵循强制性培训规定、实验室评审，以及患者保健规范等；（3）ART治疗结局虽然得到了很大的改善，但依然徘徊在0～100%之间，而且存在着对中间结局的错误使用（例如采用“临床妊娠率”而非“分娩率”），因此，要求ART以标准化的格式向政府机构报告其治疗结局。特别规定了这样详细上报程序的医疗实践活动只不过有限的几个，ART位列其中；（4）ART通常被强制实行各类质量控制程序，原因在于其治疗结局可能因微小的环境因素和操作因素而受到显著的影响。

我们不要将加诸于不育和ART的监管政策视为单纯的负担，而要看到ART有可能成为未来医疗领域开发并实施全球性RSM项目的理想试验点。

二、危险和风险

本文将描述用于改善不育和ART治疗中RSM实际效能的一些适宜的方案。在此之前，有必要对两个密切相关的不同概念（即危险和风险）进行澄清。

1．危险（Hazards）：定义为“内在”和“潜在的危害源”，指的是某一特定活动或特定局面下的一些“不可变”条件。以登山为例，“危险”源自于“高度”，这是山本身所固有的特征。因此，从性质上而言，“危险”不可能改变。

2．风险（Risks）：指的是“不愉快或不受欢迎的事件发生的可能性”。还是以登山为例，“风险”描述的是发生滑倒并导致可怕的摔落后果的可能性。

在实际运作中，必须识别出某一特定活动所内在关联的“危险”，如手术时因需要在体内使用工具所可能带来的血管损伤和细菌污染等，而对于那些可能关联于“危险”的“风险”后果（如出血、感染等）需要充分地加以评估，以通过实施适当的防范机制和／或反制措施来前摄性地防止其发生。

医疗中的防范机制包含有多种程序，致力于最大限度减少有害于患者健康的错误的发生［8］。而可能发生的有害于患者健康的错误，可经由对主要风险和危险进行分析来界定。对于因风险和危险而来的、且有害于医患健康的错误进行预防，即为RSM的核心内容和主要目标。

三、ART中的临床风险

临床风险的后果称之为不良事件（AEs）。不育治疗和ART实施过程中的AEs大体上分为三种类型：（1）凡侵入式操作所相关的寻常风险所致AEs（如出血和感染等）；（2）与ART中特有的控制性卵巢刺激（COS）相关的AEs；（3）与接受ART的特定个体的个人特质相关的AEs。

（一）凡侵入式操作所相关的AEs

1．出血和邻近器官损伤：ART病例中出血发生率不足1%，包括腹膜内出血和腹膜外出血。前者会导致腹痛、腹胀，通常出现在取卵后2～6h，超声检查可见大量腹膜内出血；而后者的超声图像显示正常的腹腔液量，常有界限模糊的腹膜后腹胀区，有触痛。两种形式的出血通常需要外科治疗，也有自发吸收者。

在取卵过程中也可能损伤到肠道、膀胱和输尿管等内部脏器，如果忽略了器官损伤的早期征象，可能会造成严重的后果。

2．感染：如果患者自身存在子宫内膜瘤，那么取卵后发生感染的可能性现实存在，而且感染的风险还比较高［4］。输卵管－卵巢脓肿甚至可能并发消耗性凝血病［5］。感染的临床表现在不同个体间差异极大，症状通常出现在取卵后数天，但有时也可能迟发（数周、数月后，甚至在妊娠过程中）［6］。治疗上或许需要手术探查，有时甚至需要行附件切除［7］。取卵过程中要尽可能地避免穿刺入这类囊肿［8］。

（二）ART特有AEs

与ART特有处理措施直接相关的AEs包括有卵巢过度刺激综合征（OHSS）、多胎妊娠及胎盘形成异常等。

1．OHSS：随着拮抗剂方案的应用，OHSS风险已大幅度降低，但OHSS长久以来都是ART的代表性并发症，在某些情况下甚至是严重的并发症，所以有必要在这里进行讨论。临床上，可根据患者年龄、体重、月经周期的规律性以及激素水平来预测患者对COS的反应程度，并作出相应的治疗调整。但就算对COS方案作出了适应性调整，仍有可能出现导致OHSS的过度反应。

在COS中，一旦OHSS风险来临，可通过一系列的措施来控制或阻止其向更严重的阶段发展。这样的措施包括：延迟HCG注射、停药“Coasting”或延期胚胎移植（Dif-ET）。如果OHSS还是出现，可采用科学治疗（维持水／电解质平衡、重复穿刺、静脉输入白蛋白、预防性使用肝素等）以有效地防止血管栓塞或器官衰竭等可怕甚至是致命性的后果。严重的AEs通常是来自于对OHSS处理不当，而非OHSS本身［9］。对于OHSS而言，适宜的治疗是阻止可怕后果的最有效手段。

2．多胎妊娠：现今的ART治疗中，有两个方面需要加以权衡。一方面是大多常规性移植2个胚胎，如此带来了30%～50%的双胎妊娠，而另一方面则是单胚移植的妊娠成功率相对较低。在各项指标都非常有利的情况下，实施选择性单胚移植（eSET）可最大限度地降低双胎妊娠率，同时对临床妊娠率的影响轻微。近年来，对囊胚期胚胎取滋养层细胞活检进行综合性染色体筛查（CSS），然后移植单个整倍体囊胚，可取得等同于未经筛查的双胚移植的妊娠率［10］。

3．胎盘形成异常：近来有多篇文章描述了在ART治疗中特定产科并发症发生率的增高，包括如ART妊娠中先兆子痫、出血、小于胎龄儿等。虽然ART和不育在其中起何作用难以确认，但有研究观察到采用冻融胚胎移植（FET）者中这些问题的发生率要低得多［11］。

ART妊娠的产科问题绝大多数（甚至全部）可能来自于COS中子宫内膜异常引起的胎盘形成异常，而FET则没有这种问题。与自发妊娠相比，ART妊娠者观察到更大的胎盘和更高的胎盘重量／出生体重比值，也为此提供了支持证据［11］。

（三）个体因素促成的AEs

ART中的第三类AEs是那些由接受ART治疗的个体所特有的风险或易感性所致者。这类个体风险包括有可引发AEs的不良血管事件、细胞遗传学异常以及子宫缺陷等。

1．血管性AEs：有些患者可能有发生血管栓塞（VTE）的倾向性。这类患者，尤其是有个人／家族VTE史者，在ART过程中需要给以肝素预防性治疗。在做不到对止血相关的基因变异进行常规检测的情况下，特别关键的是需要认识到，OHSS能将VTE风险提升100倍之多。不过，FET中并未观察到增高的VTE风险，由此进一步支持临床上对于延迟胚胎移植的选择。

如果未能预先辨识出那些有VTE特定风险的妇女，可能会带来致命的后果。不良VTE事件发生之前，通常并没有明显的临床症候，这一点同OHSS不一样。所以，预防的关键在于鉴别出那些可能需要在ART中给以肝素预防性治疗的风险个体。考虑到问题的严重性，我们建议，对于每一位拟行ART治疗者，都必须用完全相同的语句问及同一个问题：“你有过凝血块么？你家族中有人因心脏病或是没有任何明显原因而死于50岁之前么？”使用标准化的问句时，所得到的否定回答或许更为可靠，但不保证一定如此。

各种AEs风险有着不同的发展变化，因而每种风险需要有不同的防范机制来有效地加以预防。

2．细胞遗传学AEs：引发AEs的遗传风险指的是那些带有可能性威胁的个体病症，如脆性X前突变可导致男性子代脆性X智力迟缓、特纳综合征患者可能在孕期发生致命性主动脉破裂等。

3．子宫形态异常所致AEs：子宫形态异常（如肌瘤、瘢痕等）可能给妊娠带来更高的产科并发症风险，某些情况下需要采用eSET甚至代孕来规避这类风险。

四、航空安全对医疗安全的启示

正如最近的系列文章所综述［1－3］，受航空业安全举措的启发，在医疗上带来了广受赞誉的各类安全措施，其中就包括了著名的“检查清单”（Checklist），这是飞行员在执行飞行之前所必须完成的各项安全检查细则。这类心系安全的措施已经被用于医疗行业，包括检查清单、术前讨论会、医疗团队配合［12］。在许多（但远非全部）手术室和监护室已经采纳了这些手段，并且在根除重大错误（如3W，即错误的患者、错误的体侧、错误的器官）方面取得了高度的成功。一份简单的术前检查清单就降低了47%的手术死亡［13］。

然而，这些受航空安全启发的安全措施虽在手术室证明为高度有效，但并未进入医生的办公室。因此，上面提到的那些措施对于减少更基础性的医疗错误（如误诊、不正确的手术指证等）并未起到多少作用，而正是这类基础错误构成了重大的问题，并且依然是导致很多不必要伤害的原因。在2008年，美国妇产科学会（ACOG）成立了一个特别工作组，针对在门诊设施中实施安全措施和程序进行研究并提出推荐意见，其在一定程度上促成了更全面性《卓越门诊实践的安全性认证》（SCOPE）项目的开展。本文所讨论的RSM程序旨在应对不育专业中的风险和安全性问题，并将医生办公室纳入其中，因为涉及风险的操作通常是在那里启动并执行。需要注意的是，RSM是被视为对已经存在于ART之中的现有质量控制系统（如国际标准化组织的认证项目［7］及其他认证程序）的补充，而非一个竞争性系统。出于前面给出的理由，我们相信，不育和ART有可能成为进一步开发和实施全球性RSM项目的理想的医疗领域。

五、“安全为本”的医学教育

（一）学术教育及职业培训

在医学教育中，一直存在着学术教育和职业教育的困惑。一般而言，医学包含有高度复杂且具科学根源的各类程序，这就意味着需要对于前沿性生物科学的全面理解和对于一系列高科技医学发明的熟练掌握，比如当今科学成就的衍生品——医学遗传学等。在本质上，学术教育的目的是经由对各种相关分支技术的广泛学习而达成知识的融会贯通，这需要在医学院校数年的学习。

相反，职业教育追求的是对医学专科或亚专科技能的掌握，需要具有良好组织和管理的培训，并且必须植入“安全为本”（safety inside）的教学理念，目前在后一点上还差得很远。一些监督委员会和教育理事会（如美国妇产科医学委员会及欧洲、澳大利亚和加拿大的等同机构）明确规定不育及ART培训课程必须有实际操作培训（Hands-on training）或进修培训（Fellowship-type tranining）环节，但针对是否开展了合适的培训进行实际监督时，主要（甚至完全）依靠是对学员进行考试，而更有效地监控职业培训质量的措施则还需要有对于培训机构更严格的监管计划，由此确保在培训项目实施过程中，对整个培训课程进行监管，以达成管理委员会或理事会所规定的各项要求。

图1给出了就进修培训中的教辅材料特别示例。在该模式中，针对不育和ART的教育含两次为期一周的课程（初始及验证科目）以及贯穿于整个培训的9个高级教育模块。这9个模块包括如下主题（每个模块为期3天）：

模块1：排卵生理学及排卵异常病理学。排卵、排卵过少及无排卵、诱发排卵、控制性卵巢刺激（COS）、黄体支持（LPS）。

模块2：外科与不育：子宫内膜异位症，卵巢囊肿、子宫肌瘤、子宫及输卵管形态异常；腹腔镜探查术在不育症诊治中的作用。

模块3：卵巢功能及功能异常与年龄老化。卵巢储备概念、绝经及过早绝经。

模块4：生育与不育流行病学及长期趋势。种族差异、族群差异。

模块5：胚胎学，不育及ART中的生殖系统组织学；遗传学（I）：用于植入前遗传学筛查（PGS）的滋养层活检和胚胎／卵母细胞质量评估。

模块6：不育和ART中的安全风险管理（RSM）：确定危险和风险，错误及错误管理原则。知识演进原则：临床研究基础知识，方案的概念、实际运作、数据分析及报告（口头及书面）；评读原则。

模块7：身心和谐，不育与生殖。心理学及社会心理学问题。

模块8：遗传学（II）：胚胎异常及胎儿畸形筛查，植入前遗传诊断（PGD）。

模块9：“Medicalship”原理。这里的 Medicalship是一个类同于“航海技艺”（seamanship）和“飞行技艺”（airmanship）的新概念。

（二）三层次中心教育单元（CEU）

用于职业培训及学术教育的教辅材料传统上是课本式的教学大纲或其他形式的文档。我们抛开传统的做法，开发出一种中心教育单元（CEU），用于不育及ART的实际操作培训或进修培训的各个环节。与传统的课本式教辅材料相比，CEU的独到之处在于它将所有的相关教学材料存储于循序渐进的三层次格式。如图2所示，三个知识层次从浅入深分别为“必须了解”（Must know level）、“最好了解”（Nice to know level）及“专家级”（Expert level）。

（三）从“飞行技艺”导出新概念“医疗技艺”

航海技艺（Seamanship）指的是与水上操纵船舶相关的才能、技术及业务活动，人们以此类推创造出“飞行技艺”（Airmanship）一词，用来描述涉及操控飞行器的全部技能和专项技术。飞行技艺的定义后来又进一步扩展到涵盖“始终坚持运用良好的判断和充分的技能来完成飞行任务”，由此，飞行技艺一词也就意味着对于环境的高感知状态，这里面包括了对于自身、飞行器、团队以及风险等的充分了解。因此，飞行技艺不仅仅是对于技能或技术的衡量，也表现出飞行员对于飞行器、操作环境以及对于自身能力的理解。除了表示有能力以充分的技能和精准度来操控飞机之外，飞行技艺还暗示了行使准确的判断力以保障最大限度的安全有效操作。

鉴于航空业运转体系在保证高度安全性和高度效能方面的非凡成效，值得将其拓展到包括医疗在内的其他领域。出于这种考虑，我们创造出类同于飞行技艺的“医疗技艺”（Medicalship）一词，用于定义医师执行安全有效操作所必备的技能和知识。“医疗技艺”在不育和ART专业则意味着有能力对那些不育但有生育意愿的患者提供专业性关爱，并提供最恰当的治疗。

六、报告错误（Error reporting）

将实际操作中出现的错误上报是RSM的关键步骤，而无论这些错误是否带来了伤害性后果。要养成报告错误的习惯就必须克服人们天性中在出错或犯规后的避隐特质。对于那些未造成后果的错误及安全过失，我们每个人的天然反应似乎都是趋向于尽力弱化。然而，对于那些看上去未造成不良后果的错误给以不当容忍，或是当错误导致伤害性后果时谴责个体责任人，都无助于提升安全性。

出现错误时绝不应不管不顾，而应当进行处理。航空业已经清楚地表明，认识错误是改善安全性的关键。要认识错误就意味着需要启动有效的错误报告手段。航空业所认同的错误报告模式有自动报告、强制报告和自愿报告三种。

1．自动报告：自动报告在提升航空安全性上发挥了重要作用。自动报告在性质上可消解人们在错误发生后根据后果程度进行决定的倾向性。在航空管理中，设置有飞行记录仪来自动报告飞行中的一些不寻常事件，如过大角度着地等。出现问题时通常首先要问的是发生了什么？有些情况下错误的发生有着充分的理由，但更多的情况则是过大角度着地是出自于一系列普通错误。关键性的第一步是去了解到底发生了什么，由此展开分析并最终做出相应的修正。由自动报告的不寻常事件所引发的调查，所获信息在行业内共享，由此所有人都能从他人的错误中汲取经验和教训。重要的一点是，航班所有成员（飞行员及其他空乘人员）都受到类似的监察，即所谓的“公平文化”。这最终有助于促成自愿性的错误报告模式以及将所有错误（无论后果如何）均作为需要加以调查的事件来对待的文化氛围［14］。

自动报告的目标在于改变人们对于错误分析（error analyssi）的态度，但在不育和ART领域，自动报告仍处于相当初级的阶段。实施不同形式的自动报告，目的在于促进建立并维持一种“公平公正的文化”。

2．强制报告：一些特定事件必须加以报告和分析，即便是那些不一定是错误所致者。例如在ART中，任何治疗项目都应有相关机制，用来对于未获卵或受精失败等事件进行回顾分析。未获卵或受精失败可以是出于医疗错误，也可能出于患者的个人特质，一旦发生都必须对临床和实验室操作进行回顾分析。患者在接受ART治疗时处于不良“流程后果”（process outcomes）的高风险之中，应当将实际结局同基于已发表资料的预期结局进行比较（基准校验）。基准校验是比较结果和评估效能的重要手段，尤其是在没有错误发生的情况下。

管理机构应要求医疗机构向患者披露医疗错误（包括任何的意外不良事件）。在不育和ART的RSM中应当内置有针对患者的自愿性全面披露程序。

3．自愿报告：非惩罚性自愿报告是保障医疗操作安全性的关键。支持非惩罚性报告的文化氛围将有助于医疗错误和AEs的早期发现，并带来改进行动（如必要时重设系统等）。如美国联邦航空管理局（FAA）颁布的“航空安全行动项目”（ASAP）准许飞行员（或操作员）秘密提交事故报告。然而，在医疗实践中不会自然出现自愿报告，需要有强力的领导和激励措施。我们的个人意见是，医疗中的自愿报告应当封印于某个受保护区间，不得用于法庭证据。这样隔绝律师和当事人之间信息交换的模式可做为建设性模式。

七、“说你所做”（Say what you do）方案让医生负起责任

1．公认准则之内的操作程序：RSM中的一个核心问题是对于那些拿来运用并加以遵循的操作程序进行界定并标准化的必要性。这一点对于检测和监控偏差是必要的。然而，对于特定程序的制订和遵守在临床医疗中并不能做到始终如一，由此成了贯彻实施安全系统（其内容远超检测清单及类似措施）的绊脚石。

ART实践在某些方面就陷入了规则和条例的麻烦之中。有的管理条例过于复杂，不符合当前形势，或不便于实际执行。在管理措施不切实际或过时的情况下，为了维持系统的运作和程序的流转，就只好做出一些非法偏离和违规操作。此外，以安全性为目的而进一步拓展规则和条例，更是为已经纠结的系统雪上加霜。正如我们所观察到的，简单地添加规则和条例并不是通向更安全ART实践的最好路径。

RSM需要创造出医生－管理者间新的互动模式，以提升安全性并将可靠性深植于实践文化之中，而非仅仅去制定出更多的规则。

2．ART与认证制度：在许多国家中，监管当局推荐采用传统的质量保证体系，如国际标准化组织的认证体系（ISO认证）来应对ART所固有的弱点和风险［15］。

这类针对ART程序的认证文件如协议书和标准操作程序（SOPs）是RSM的良好起点，它们提供了一种让RSM可建立在其上的“说你所做”方案。然而，风险管理并不总是质量保证和认证程序的固有元件。RSM自身有深具安全意识的日程，可与ISO协同运作，但不仅限于ISO。RSM与质量系统就像是计算机程序与操作系统，它们协同工作，但各自不同。