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Hindawi Publishing Corporation Scientifica Volume 2012, Article ID 980812,16 pages http://dx.doLorg/1O.6064/2012/980812

Review Article Public Health Impact of Legal Termination of Pregnancy in the us: 40 Years Later

John M. Thorp Jr.

Department of Obstetrics and Gynecology,School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA

Correspondenceshould be addressedto John M. Thorp Jr.;[email protected]

Received6 September2012;Accepted15October 2012

AcademicEditors:M. W.Davies,T.B.Henriksen,and J.Keelan

Copyright @ 2012John M. Thorp Jr.This is an open accessarticle distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution,and reproduction in anymedium, providedthe originalwork is properly cited.

During the 40yearssincethe USSupremeCourt decisionin Doe versusWadeand Doe versusBolton,restrictions on termination of pregnancy (TOP) were overturned nationwide.The use of TOP was much wider than predicted and a substantial fraction of reproductiveage women in the U.S.have had one or more TOPs and that widespreaduptake makes the downstream impact of any possibleharms have broad public health implications.While short-term harms do not appear to be excessive,from a public perspectivelonger term harm is conceiving,and clearlymore studyof particular relevanceconcerns the associationsof TOP with subsequent preterm birth and mental health problems. Clearlymore research is needed to quantify the magnitude of risk and accuratelyinform women with the crisisof unintended pregnancyconsideringTOP.The current US data-gatheringmechanisms are inadequatefor this important task.

1. Introduction randomized controlled trials for a procedure that cannot be ethically assigned by chance, the inherent difficulties in syn- This is a paper written on the 40th anniversary of the US thesizing observational data, and the ethical controversy that Supreme Court decisions in Roe versus Wade and Doe versus swirls underneath this topic. Meta-analyses on appropriate Bolton, in which termination of pregnancy (TOP) restrictions outcomes are included in the paper when they have been were overturned in all fifty states [1]. This profound socio- done. cultural shift in paradigm and practice has had substantial Next, the paper is geographically parochial and limited to impact on the lives of women and families in the US and the US. This is due to the limitations of the author and the fact around the world. I am writing from the perspective of an that the US experience is often generalized to the rest of the obstetrics and gynecology clinician who has witnessed much developed world. Articles from other countries are cited for of this change during his career. A similar approach from comparison purposes. a personal perspective has been )used by others on earlier The language used to describe these procedures is fraught anniversaries [2-7]. with inaccuracy and often overlaps with clinical language Rather than the traditional recitation ofiimitations at the used to describe spontaneous pregnancy loss. This is confus- end of the paper, I have chosen to inform the readers of ing to readers and at times alarming to patients [8]. In this those a priori. Thus, it can process the evidence cited and paper the phrase "termination of pregnancy" (abbreviated as conclusions made with those caveats in mind. My hope would TOP) will be used throughout. Use of the abbreviation TOP be that by providing context from the outset, the reader will reflects the editorial policy of the British Journal of Obstetrics be able to more thoughtfully consider the material presented. and Gynaecology and has been forged after numerous discus- First, this is not a systematic review. The relevant litera- sions among the editors, to which the author has been privy. ture has not been systematically searched, read by multiple Finally, and most importantly, the ethical principle of reviewers, graded against a standard, or quantified by meta- autonomy precludes random assignment to TOP. Thus, analysis. A more subjective and qualitative approach has randomized controlled trials of TOP exposure versus no been chosen. This approach was selected due to the lack of exposure are impossible to conduct. By definition there is no Case: 3:13-cv-00465-wmc Document #: 245-1 Filed: 06/11/14 Page 2 of 17

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"Level One" or "Grade!\' evidence about TOP [9]. Given that of all identifiable TOP providers by the Gutlmacher Institute. women who choose TOP differ from nonpregnant women, Reporting is voluntary and the surveys are done at irregular those who continue a pregnancy, or those who suffer a intervals up to five years apart. The Gutlmacher Institute has spontaneous loss, unmeasured residual confounding plagues a clear political agenda and anyone perusing their website investigators and readers trying to understand the biologic would be hard pressed to not describe it as an advocacy group implications of the procedure. The appropriate nonexposed [24,25]. control is a source of much disagreement. Whether one The second source is the annual "abortion surveillance discerns true benefit or substantial harm from observational report" amalgamated by the US Centers for Disease Control data about TOP, conclusions will always be limited along (CDC). Beginning in 1969, state health departments have those lines. voluntarily provided annual reports on TOP procedures and patients. These data are incomplete due to the wide variability in state requirements for reporting of TOP procedures, the 2. Background voluntary nature of participation with some states choosing to not do so periodically, marked variation in the information Before the US Supreme Court decisions mentioned earlier each state obtains, and the lack of specific funding for were issued, TOP in the US was severely restricted. With TOP data accumulation. For instance, the large US State of that decision, access to the procedure was greatly expanded California has not reported in the past decade. Thus, any and the uptake of TOP procedures was higher than experts report on TOP epidemiology from the US is fraught with predicted. From most recent sources, a prototypical US numerous assumptions and lack of any clear standardization woman will have two children [10, 11]. Nearly half of all [26-30]. US women will have an unplanned or unintended pregnancy The incidence of TOP is usually stated in one of three (when intentionality is broadly defined) and somewhere ways: total number, rate, and ratio. The TOP rate is the around half of those will elect to undergo TO P.Thus, between number of TOP procedures per 100 women aged 15 to menarche and menopause, in the US, one out of three 44 years (so-called reproductive age). The TOP ratio is the women will undergo TOP. This makes TOP "one of the most number of TOP procedures per 100 pregnancies. Pregnancy common medical interventions" [12-15]. in the ratio includes live births and TOPs and it excludes In the US, approximately 1.2 million TOPs were per- spontaneous pregnancy losses and intrauterine fetal demises. formed in 2009, while there were 4.5 million live births With these caveats in mind, and despite the limitation of [13]. Around 90% of TOPs in the US will be done in the TOP epidemiology, the utilization of TOP soared dramat- first trimester, with the remainder in the second and third ically after the US Supreme Court decision. TOP numbers trimesters. Around 1-2% of TOPs in the US are done because peaked in 1988 to 1.59 million, with the peak TOP rate of serious maternal illness, such as cancer or pulmonary in 1990 of 27.4 TOP/100 women aged 15-44 and the peak hypertension, or an abnormality detected in the fetus, such TOP ratio in 1983 of 30.4 TOP/IOO pregnancies. From 1973 as trisomy or neural tube defect [14]. Until the past decade, to 2008, Gutlmacher estimates that 50 million TOPs were almost all TOPs in the US were performed surgically. Since performed. In 2008, US women had 1.2M TOPs with the 2000, medical TOP has become more widely used, building TOP rate being 19.6 TOP/lOOO women aged 15-44 years on experience from Western Europe. Medical TOP involves [24,25]. use of the progesterone antagonist and the Using estimates from the Gutlmacher Institute patient prostaglandin . Around 10% of TOPs in the US survey, US women in their 20s account for 57% of all TOPs. are completed medically [16,17]. Adolescents under 20 obtain 18% of TOP. As to race, in 2008 among women choosing TOP, 36% were non-Hispanic white, 3. Epidemiology 30% were non -Hispanic black, and 25% were Hispanic. Single women (never married and not cohabitating) had 45% of Unlike numerous other countries, the US does not have a TOP procedures in that year and 61% of women seeking TOP systematic method of keeping track of TOP procedures [18- were mothers to at least one child. In terms of socioeconomic 22]. TOPs are not registered by the government, and there status, 42% of women seeking TOP have incomes below the is no mandatory reporting so the true incidence cannot US poverty level [24,25]. In the month they conceived, over be ascertained. Moreover, TOPs cannot be linked to other half of the women seeking TOP were contracepting with the sources of health data such as birth or death certificates, majority using oral contraceptives or condoms. As one might thereby making precise calculation of mortality rates or sub- predict, inconsistent use of contraceptives in the preceding sequent birth outcomes impossible. This lack of registration month is common-76% of pill users and 49% of couples of TOP in the US means that observational data from other relying on condoms [29,30]. countries is more reliable in determining short- and long- Almost 90% of TOPs are done in the first trimester (12 term health effects. To quote a famous US women's health weeks from the last menstrual period). Somewhere around epidemiologist, the current situation could be described as 1% of TOPs in the US are performed after 20 weeks. These "garbage in, garbage out" [23]. numbers have remained steady over the epoch this paper Two proximate data sources are used in the US by those covers, although there has been a shift toward lower gesta- interested in TOP epidemiology. The estimated number of tional ages with more TOPs done in the first trimester over TOP procedures in the US is obtained from periodic surveys the 40-year epoch being reviewed [26-30]. This phenomenon Case: 3:13-cv-00465-wmc Document #: 245-1 Filed: 06/11/14 Page 3 of 17

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has been attributed to the approval in 2000 by the US Food 4. Maternal Mortality and Drug Administration of mifepristone for medical TOP. Medical TOP regimens become less effective after 9 weeks As described earlier in this paper, the US TOP epidemiology and many protocols limit their use thereafter. Concurrent is plagued by the lack of a TOP registry and reliance on with widespread legalization of TOP in the US in 1973 was what is largely survey methodology [38]. Because this system the introduction of (or suction curettage) is voluntary, and also due to the inherent reluctance of which widely became the mechanism of choice for surgical surgeons to. disclose serious complications such as death, TOP. This procedure can be utilized for TOP up until 13 underreporting is a major problem [39]. Comparing CDC weeks and includes cervical dilation, either chemically or Abortion Surveillance reports to deaths reported in the mechanically, and suction to empty the uterine contents. popular press demonstrates that, for instance in 1989, four Procedures for second trimester TOP include induction of deaths resulting from TOP did not make it into the state's 'labor chemically or mechanically, hysterotomy, hysterec- statistics (the CDC reported zero deaths in that particular tomy, or (D&E). D&E TOP is the year) [38]. most common technique in the US, accounting for over 95% In contrast to the US, countries with mandatory reporting of the procedures done after the firsttrimester [31-35]. and the ability to link birth, abortion, and hospital registries In the early 1970s, most TOP procedures were done show increased rates of mortality above US estimates and in acute care hospitals. Over time the TOP site of service increased relative risk of death after TOP when compared to has shifted from the hospital to the outpatient .setting. By women having a child. Similar findings have been reported 2005, only 5% of TOPs were done in the hospital. Medical in the US from administrative databases, such as publicly- TOP approaches have allowed for procedures to shift from funded TOPs from California [38]. This casts further doubt the medical setting to the home. Even second trimester on contemporary US surveillance systems to generate reliable D&E procedures for TOP can be done in the outpatient estimates for TOP-related mortality. setting [36]. Compared to other developed countries, the US Unlike the identification and ascertainment of TOP- TOP rate is substantially higher than Finland, Switzerland, related deaths in the US, pregnancy-related deaths are Germany, and the Netherlands where rates range from 7 systematically sought, identified, and investigated by state to 11/1000 women and ascertainment is far better due to maternal mortality commissions. These entities have the standard registries and record linkage capacity. Only Sweden ability to confidentially obtain medical records, review clin- .in 2005 had a TOP rate similar to the US at 20 or so ician notes, and determine if a pregnancy-related death was TOPs/lOOO reproductive-age women. Women in European preventable. The commissions have operated since the early countries are more likely to undergo medical TOP than are 20th century. Over the past 30 years more and more US US women [18-21]. jurisdictions allow electronic linking' of birth and death Thus, despite expert prediction that easing TOP restric- certificates. This automated connection process has greatly tions in the US would culminate in TOP rates less than increased the number of pregnancy-related deaths identified 5/1000, the utilization of TOP has been much higher than and allowed a more thorough understanding of the epidemi- anticipated. This phenomenon has only begun to decline 010gy of childbirth. TOP lacks any formal registry and thus in the past decade despite the widespread availability and linking TOP with death is not possible [38]. improved safety of effective contraceptives. One in ten US TOP is a surgical procedure usually completed in min- women will have had a TOP by the age of 20, one in utes, whereas childbirth encompasses the 40 weeks of preg- four by 30, and one in three by 45. Each year in the US nancy and 6 weeks postpartum. Thus, TOP and its associated 2% of women between 15 and 44 years of age have a major complication, death, is like a single snapshot, whereas TOP. This has caused experts to label TOP as the "most pregnancy and pregnancy-related death are like a feature common of medical interventions" [28-30]. Beyond ethical length film. Moreover, any death during or 6 weeks after and demographic concerns with widespread use of TOP in pregnancy is labeled pregnancy related and categorized as the US, it has significant epidemiologic implications. Even direct or indirect. A woman who underwent TOP in the first modest elevations in hazard ratios associated with TOP trimester, suffered profound depression, and four weeks later would have profound biologic effects due to its common use committed suicide would not be labeled a TOP-related death in the US For instance, if the hazard ratio for preterm birth even if the TOP was known about. Conversely, a woman associated with TOP is 1.3, then the population attributable delivering at term who had a similar series of events would be risk would be 3.2% and therefore over one-quarter of preterm labeled a pregnancy-related death. This differential window births in developed countries would be attributable to TOP of attribution makes direct comparisons misleading. [37]. Harms or benefits associated with such a commonly One recent study from Chile explored 50 years of reg- used procedure, even if rather modest, would ripple through istry data from a country that prohibited TOP in 1989. a population and have a large impact. Thus, the need for Such restrictive legislation would have been predicted by accurate incidence estimates and linkage to other health many women's health epidemiologists and clinicians to records is important to the large number of women who will greatly increase childbirth-related deaths if TOPs were truly have a TOP, the 75% ofthose having TOP who will try to have safer. The contrary occurred with maternal mortality from a child after TOP, and to a society interested in the health of pregnancy and childbirth continuing to fall even after the women and children. TOP restrictive law was passed. Increasing education levels Case: 3:13-cv-00465-wmc Document #: 245-1 Filed: 06/11/14 Page 4 of 17

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of women had the most favorable impact on the falling 5. Short-Term Harms childbirth-related maternal mortality rates [40]. TOP epidemiologists lump all deaths together across the Like all other elective surgical or medical procedures, TOP full spectrum of gestational age despite the well-known fact carries the inherent risk of bleeding, infection, and damage to that TOP morbidity and mortality increase with advancing other organs in the genitourinary and gastrointestinal tracts. gestational age. The fact that TOP most often occurs in In addition, TOP procedures have unique risks ofincomplete the first trimester in the US skews the aggregated mortality emptying of the uterus and obfuscation of the diagnosis numbers used in most comparisons toward the time in of ectopic pregnancy [49]. As mentioned in the mortality pregnancy where TOP procedures are relatively safer. The section, the likelihood of harm is dependent on gestational risk of death associated with TOP increases from one death age with risk directly proportional to gestational age. One US for every one million TOPs at less than 9 weeks to three per study estimates a hazard ratio of 1.38 for TOP complication one hundred thousand TOPs at 16-20 weeks to 10 per one for each week after a TOP procedure is performed with the hundred thousand at 21 or more weeks in the US [27-30]. same being true for TOP-related mortality [50]. Bleeding or hemorrhage (defined as estimated blood Reardon and Coleman [41] just published an article loss > 500cc) occurs in up to 1% of TOPs in the first which looked at maternal mortality for an epoch of 25 trimester and up to 2.5% of second trimester TOPs. Causes years using Danish birth and death records. Their cohort of excessive blood loss include cervical laceration, uterine consisted of 463,473 women and they used TOP in the perforation, atony, and retained pregnancy (products of first pregnancy as the exposure of interest, controlling for conception). While atony may respond to uterine massage or pregnancy outcomes in subsequent gestations. For women administration of drugs that cause the uterus to contract, the having TOP at <12 weeks, cumulative mortality rates were other complications will require additional surgery. Rarely higher from 180 days to 10 years from the index pregnancy. blood transfusion and hysterectomy will be needed [51]. The association between TOP and cumulative mortality was Uterine perforation or puncture by the suction cannula similar but stronger for TOP >12 weeks gestation. The or sharp curette during the TOP occurs in 10-15/1000 comparison group was women who delivered after 20 weeks procedures. Risk factors include increasing gestational age, gestation. While far from definitely answering the question, uterine leiomyomata, and surgeon inexperience. Perforations the linkage study does cast doubt on the claim that TOP is can damage pelvic vessels, bowel, bladder, and tubes and safer than pregnancy continuation. ovaries. This complication is the most common inciting event Another problem inherent in comparing aggregated for subsequent laparotomy or laparoscopy to inspect the deaths for TOP and pregnancy is the failure to control for pelvis for organ damage. "Silent" or unrecognized perforation important confounders other than gestational age when the with organ injury can have severe consequences [52]. TOP is performed. Women seeking TOP in the US are Likewise, the cervix (opening to the uterus) can be torn or younger and presumably healthier, although they are more lacerated during a TOP. The likelihood of cervical trauma can likely to be single and of lower socioeconomic status which be greatly reduced by cervical preparation with Laminaria have negative health effects. Thus, failure to control for or pharmacotherapy prior to TOP [53-55]. Up to 3% of important confounders makes direct comparisons of crude second trimester TOP procedures are complicated by cervical rates even less accurate [42-46]. trauma [56]. Unrecognized or inadequately repaired tears are In terms of lives lost, current TOP epidemiologic one proposed mechanism for the association between TOP approaches assume that the embryo or fetus has a null moral and preterm birth in a subsequent pregnancy. The trauma is status and that the loss of a potential human being (which hypothesized to culminate in cervical insufficiency. is the stated goal of every TOP procedure) should not be Failure to empty the uterus completely or recognize an considered. This failure to account for the impact of losing a ectopic gestation during TOP is rare event when ultrasound future citizen has had profound demographic consequences is used before and after TOP procedures. One concern in in countries with unrestricted access to TOP, such as the US the proposed scheme to increase access to TOP by having In a horrible twist reminiscent of the movements of nurses performing the procedure is their lack of familiarity the 20th century, some US states have even lowered barriers with diagnostic imaging. These TOP complications when to TOP with the stated intent of lowering the number of not recognized or attended to can have deleterious health individuals needing social support or mental health services outcomes, including death. [47]. These losses are not captured in mortality statistics that Infection is the most common short-term complication solely value the life of the mother. after TOP [51]. It occurs after 1 to 5% of surgical TOPs and is Despite the inherent absurdity in comparing death rates usually polymicrobial in nature [57]. Antibiotic prophylaxis from TOP to childbirth, such comparisons continue to be can reduce this risk in surgical TOP. The so-called septic done by prominent clinicians and various advocacy groups abortion is the most common presentation and usually [48]. Comparisons are inherently biased and those biases responds to broad spectrum antibiotics and evacuation of may confuse women considering whether to have a TOP any retained portions of the pregnancy. Rarely, laparotomy or continue their pregnancy. Differences in ascertainment will be needed to drain an abscess or remove an infected of deaths, duration of susceptibility to mortality, lack of uterus. There has been a recent cluster of fatal toxic shock after accounting for gestational age, and choice of appropriate medical TOP caused by Clostridium species. The epidemiol- comparison group make these comparisons a fool's errand. ogy of this complication and role of microbiotic prophylaxis Case: 3:13-cv-00465-wmc Document #: 245-1 Filed: 06/11/14 Page 5 of 17

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remains to be elucidated [56,57]. When medical and surgical 1.28-2.71). Moderate statistical heterogeneity was identified TOP procedures are directly compared, more women in the between studies and the results persisted after adjustment for medical TOP groups will require surgical evacuation and known confounders. The population attribute risk was 2.7% experience more bleeding, while surgical TOP has more and thus up to one-third of PTBs in contemporary perinatal traumatic complications [58-60]. practice in the US could be due to TOP [64]. There are over 130 published studies showing an association between TOP and either preterm birth or its surrogate, low birthweight [65- 6. Long-Term Harms 196]. In one of the larger and most comprehensive studies While there are numerous claims made asserting that TOP published to date, Klemetti et al. recently reported that has no long-term consequences beyond the immediate com- in first-time mothers, TOP was associated with preterm plications described above, careful readers will be struck birth, particularly "very early" preterm births at <28 weeks by the paucity of data on this topic, particularly from the gestation. Using the Finnish Medical Birth and Abortion US Moreover, as mentioned throughout this paper, all data Registries to link 300,858 records, they not only showed an are observational rather than experimental. Case-control association between TOP in a first pregnancy and very early studies are particularly prone to differential reporting of preterm birth, but also showed a "dose response" effect with TOP exposure and a serious illness such as a new cancer more TOPs increasing the strength of the association. They diagnosis may make a case 'more forthcoming about a TOP call for health care professionals and the public to be warned than would be a control of this sensitive issue. In the US, about the risks [197]. lack of TOP registration and thus inability to conduct cohort This phenomenon is of great importance in perinatal studies in which there is no linkage to birth certificates or epidemiology. Most risk factors for PTB, such as race or cancer registries makes all investigators reliant on self-reports multifetal gestation, are not modifiable, while TOP is mutable of TOP exposure [61]. [62, 63]. In my clinical experience, subsequent pregnancy TOP does not appear to be associated with subse- performance is of paramount importance to a woman facing quent increased risk of subfertility, spontaneous abortion, a crisis or unintended pregnancy. Up to 75% of US women or ectopic pregnancy. There has been shown a consistent, opting for TOP will have a subsequent pregnancy, so the modest association between TOP and placenta previa in a importance of the finding from public health, demographic, subsequent pregnancy. and informed consent perspectives should not be underesti- I will not belabor those findings, but turn to three mated. conditions in which the literature is more comprehensive Studies exploring an association between TOP and breast in reporting links between TOP and the health outcome in cancer have had mixed results with some showing small question. Those will include preterm birth, breast cancer, and increases in risk and others demonstrating no difference mental health problems. Each is an important women's health between exposed and unexposed women. The single meta- outcome with lifetime prevalence greater than 10%. Readers analysis found a summary odds ratio of 1.3 (95% CI 1.2-1.4) should harken back to the discussion about population [62] while a US National Cancer Institute review found no attributable risk to refresh their memories that even small effect [198], as did the Collaborative Group on Hormonal increases in risk can have profound health consequences Factors in Breast Cancer in a reanalysis of 53 studies [199]. In given the fact that one out of three US women will undergo 2002, our research group presented a novel theory based on TOP in their reproductive years. the Gail Model, which is widely used by clinicians to predict Preterm birth (PTB) prior to 37 weeks gestation is the 5-year and lifetime risk of breast cancer, and has been used as most common cause of infant death and disability in the the entry criteria for chemoprevention studies. In this model, US and complicates more than one in ten births [62]. The a term birth and lactation are protective, reducing future risk, etiology remains unclear, and concurrent with the social and thus we speculated that a woman choosing TOP and experiment of abolishing legal restrictions to TOP in the foregoing childbirth would experience a loss of protection. US initiated by the Roe versus Wade decision, the US has This would be of no mere consequence for younger women experienced an ever-increasing rate of PTB. Other changes as the younger a woman is with her first term pregnancy, the have occurred over that epoch such as increased use of greater protective effect she might enjoy. To our knowledge subfertility treatment, which increases the risk of multi- no one has gathered prospective data to test our hypothesis. fetal gestations and preterm birth. Mechanical trauma to This link, or lack thereof, remains a field ripe for further the cervix, infection, and scarring of the endometrium are exploration [61]. all putative mechanisms for how TOP could increase the The story is almost identical to breast cancer for TOP and likelihood ofPTB [63]. mental health. Individual studies are mixed, albeit numerous, In 2009, Shah and Zao, on behalf of the "Knowledge Syn- indicating harm [198, 200-300]. One meta-analysis shows thesis Group of Determinants ofPreterm/Low Birth Weight" a modest increased risk of mood disorders, suicide, and conducted a rigorous, systematic meta-analysis [37]. The substance abuse in women having TOP [301], and two world's literature was independently reviewed and 37 studies reviews by national organizations have concluded that the were assimilated. One TOP was associated with increased data are limited and no firm conclusions can be drawn [302]. odds of PTB (OR-1.36, 95% CI 1.24-1.50) and more than Problems include what will begin to sound like a familiar one TOP with increased odds of PTB (OR-1.93, 95%CI litany to readers of this paper-the limits of observational Case: 3:13-cv-00465-wmc Document #: 245-1 Filed: 06/11/14 Page 6 of 17

6 Scientifica data, lack of US registry data, recall bias, and the list goes third trimester (after viability) could be restricted except in on [303]. Again, this is an area that merits investigators' situations where a woman's life or health was threatened. attention, as the population attributable risk for the meta- Health was broadly defined in the two decisions to include analysis was that up to 10% of mental health problems, in mental and emotional health. women who experience a disproportionate share of mental Since 1973, the US Supreme Court has explicitly declined health problems, can be linked to TOP. to overturn its decision on TOP. Despite that hesitancy, beginning in 1989 and with subsequent rulings, the Supreme Court has diminished the constitutional protection of the 7. Clinicians Providing Top right for TOP and essentially degraded the standard of "strict scrutiny" that was originally assigned. The fruit of In the US after Roe versus Wade in 1973, there was an that change has been various state statutes requiring things increase in the number of TOP providers up until 1982. such as a proscribed waiting period, mandatory informed After 1982, the number has steadily declined and by 2005 consent, parental involvement for minors seeking TOP, and the total was close to the number in 1973. Coincidental with data reporting requirements. In 2007, the US Supreme Court this decline has been a shift in service location from the went even further in Gonzales versus Carhart which upheld inpatient to the outpatient setting, where over two-thirds of the "Partial Birth Abortion Ban Act of 2003:' That opinion TOP procedures in the US in 2005 were performed. Only allowed states to prohibit certain TOP techniques and for the 23% of TOP providers offer procedures after 20 weeks and first time there were no exceptions allowed for the health of only 11% after 24 weeks. TOP seems to be preferentially done the mother [309, 310). in urban setting with 87% of US counties lacking a TOP With the gradual relaxation of strict scrutiny, state leg- provider [304]. islatures and Congress began to regulate TOP in the US In In response to a decline in the number of US OBG 1976, the Hyde Amendment prohibited use of federal funds residents opting to not learn how to perform TOPs, and to pay for TOP procedures. States followed suit to forbid the the subsequent decline in TOP providers, a privately-funded use of state dollars (32 states and the District of Columbia) initiative was started in 1999 to try to reverse this trend. for TOP and to regulate insurance coverage for both public Over 40 US residencies have affiliated with the program. and private employees. Other restrictions include licensing The program is named after Kenneth Ryan, who was the and inspection requirements for TOP facilities, prohibition longstanding OBG Chair at Harvard and an advocate oflegal of certain procedures, mandatory information and waiting TOP. Whether training is "routine" or "optional" remains periods, required parental involvement, conscience clauses a source of much discussion [305-307]. Federal funding of for both clinicians and institutions, and limitation of graduate graduate medical education in the US provides residents with medical education training requirements. Mandated ultra- some protection on conscience and the freedom to choose sounds prior to TOP with patients giving the option to view whether to participate in TOP or not. It remains to be seen the images is the latest area where new state laws are trying to how the Affordable Care Act will impact conscience and regulate TOP practices. TOP was a major issue in passage of resident decision-making about participation in TOP. the Affordable Care Act and how those laws will affect TOP funding and training for individuals and institutions await 8. Law, Policy, and the Judiciary the Act's implementation [306]. Powerful public interest groups have risen on both sides of the restriction issue and TOP is a contentious issue in US politics and culture and is are often on opposite sides of lawsuits to overturn new laws a theme of both state and federal executive and legislative (310). campaigns. Some of the contention is no doubt due to the fact that in 1973 the US Supreme Court in Roe versus Wade and Doe versus Bolton decreed an unrestricted right to TOP 9. Conclusion within the privacy provisions of the US Constitution. That decision overrode local restrictions in all states and territories The natural experiment in abolishing most restrictions on and shifted the grounds for settling disputes on TOP from TOP initiated by the US Supreme Court in 1973 has proven the legislative branch to the judiciary. Moreover, the decision the fallacies inherent in expert predictions. First, uptake of overstepped cultural and religious prohibitions founded on this procedure by women was far greater than predicted the premise that fetus or embryos are at least potential and in 2012 one out of three women in the US will have individuals deserving moral status and societal protection a TOP by the age of 45 [310, 311]. Second, a myopic [308]. focus on short-term complications has documented, albeit The 1973 decision did not find the right to TOP to be incompletely, the relative safety of the procedure at early absolute, but did extend to that decision the highest degrees gestational ages, but failed to adequately explore the long term of constitutional protection, so-called strict scrutiny. Under health consequences. This is of particular importance with the doctrine of strict scrutiny no state can restrict TOP unless such widespread uptake of TOP where even modest increases there is a compelling state interest. The majority opinion in hazard ratios can have a huge impact on a populations found no state interest that would allow restrictions in the health. The example of PTB stated herein is illustrative of first trimester, only the health of the woman could be used this impact. The health impact of TOP is further befuddled to restrict TOP in the second trimester, and TOP in the by a paucity of reliable epidemiologic data on TOP and Case: 3:13-cv-00465-wmc Document #: 245-1 Filed: 06/11/14 Page 7 of 17

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DEATHS ASSOCIATED WITH ABORTION interest could not impose a burden on the woman's own health needs.2 The third reason, to protect the life and health of the woman, was COMPARED To CHILDBIRTH- upheld as a legitimate and compelling state interest. However, the A REVIEW OF NEW AND OLD DATA AND Court also noted that, due to medical advances, abortion in early pregnancy, that is, prior to the end of the first THE MEDICAL AND LEGAL IMPLICATIONS trimester, although not without its risk, is now relatively safe. Mortality rates for women undergoing early abortions, where the procedure is legal, appear to be as low as or lower than the David C. Reardon, Ph.D. *, Thomas W. Strahan, J.D. t, rates for normal childbirth. Consequently, any interest of the State in protecting the woman from an inherently hazardous John M. Thorp, J!., MD. Martha W. Shuping, MD. ** procedure, except when it would be equally dangerous for her to forgo it, has largely disappeared.3 Using comparative mortality rates (abortion versus childbirth) as its marker, the Court held that "in the light of present medical knowledge," In the landmark ruling of Roe v. Wade, the Supreme Court the State could only pros€cribe or regulate abortion to protect women's identified three reasons why States might seek to proscribe or regulate health after induced abortion: (1) "to discourage illicit sexual conduct;" (2) to exercise "the State's interest - some phrase it in terms of duty - in approximately the end of the first trimester. This is so protecting prenatal life;" and (3) "to protect the pregnant woman, that because of the now-established medical fact ... that until the is, to restrain her from submitting to a procedure that placed her life in end of the first trimester mortality in abortion may be less than serious jeopardy .,,1 mortality in normal childbirth. It follows that, from and after The first reason, to discourage illicit sexual conduct, was quickly this point, a State may regulate the abortion procedure to the rejected by the Court, because it was not argued by the State and was extent that the regulation reasonably relates to the preservation 4 also inconsistent with a ban on abortion for married couples. The and protection of maternal health. second reason, the State's interest in protecting prenatal life, was the It was probably in regard to this judicial assessment of abortion's subject of much discussion (and remains so today), but this interest safety relative to childbirth that Chief Justice Berger stated that he was was substantially limited by the Court's determination that no "troubled that the Court has taken notice of various scientific and consensus exists as to when human life begins. The Court allowed that medical data in reaching its conclusion."5 In stating his concern, the the State's interest in protecting a prenatal life became more compelling as the pregnancy moved into later trimesters, but this 2 ld. at 164-65.

3 ld. at 149.

Originally published in 41d. at 163 (emphasis added). This use of comparative mortality rates as the dividing line determining when the State may regulate abortion to protect the health interests of & The Journal of Contemporary Health Law Policy2004; 20(2):279-327. women was also stated and reaffirmed in Planned Parenthood v. Casey, 505 U.S. 833, Reprinted with permission. 929 (1992).

5 Doe v. Bolton, 410 U.S. 179,208 (1973). It should be noted that the court has also made subsequent statements reflecting the belief that mortality rates for abortion are lower than for childbirth. In Stenberg v. Carhart, 530 U.S. 914,923-924 (2000), there is

I this language: "Vacuum aspiration is considered particularly safe. The procedures for Roe v. Wade, 410 U.S. 113, 148-50 (1€973). mortality rates are, for example, 5-10 times lower than those associated with carrying

CAJvvA- ~ 6~~h;t sol- Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 2 of 26 '"

Deaths Associated with Abortion Compared to Childbirth--A Review page-2

Chief Justice may have been reflecting the insight that medical opinions are often reversed in light of new discoveries. If later Table 1: Record linkage studies comparing deaths associated with research were to reveal that abortion is not safer than childbirth, and abortion and childbirth more particularly that the mortality rate associated with first trimester abortions is not lower than that for childbirth, the logic of Roe would Location Time Primary Secondary Age-adjusted require a reversal of the practical impact of the ruling.6 By Period Source Record Source Linked relative risk of establishing comparative mortality rates as the standard that to Primary death from all determines when a State's interests become "compelling," it follows Source causes for that the constitutional restrictions on the State's right to proscribe or aborting regulate abortion would necessarily contract if and when it were found compared to that the mortality rates of abortion were higher than mortality rates delivering associated with childbirth. women Thirty years later, the best available evidence now contradicts the ll "established medical fact" relied upon in Roe. Recent analyses of large Finland 1987-94 9,192 death Birth and 3.5 over 1 year medical databases linked to death certificates have now shown that certificates abortion when mortality rates associated with abortion and childbirth are registries for the examined using a single uniform standard, significantly higher one year prior to mortality rates are associated with abortion (see Table, 1).7,8 These death record linkage studies have demonstrated that pregnancy-associated l2 deaths are actually two to four times higher for aborting women Califomia 1987-98 173,279 women Death certificates 2.0 over 2 years compared to delivering women. with a for subsequent While no state has yet attempted to regulate or proscribe abortion pregnancy eight years 1.6 over 8 years based on these findings, it is likely that the key "medical fact" relied outcome in upon in Roe will come under much closer judicial scrutiny in the near 1987 paid by Medicaid insurance the fetus to term," [d, (citing OBSTETRICS:NORMAL& PROBLEMPREGNANCIES1251 (Steven G. Gabbe et al. eds., 3'" ed. 1996); Herschel W. Lawson et aI., Abortion Mortality, United States, 1972 through 1987, 171 AM. J. OBSTETRICS& GYNECOLOGY 1365, 1368 (1994); MAUREENPAULET AL., A CLINICIAN'SGUIDETO MEDICALAND SURGICALABORTION108-109 (1999». None of these cited sources, however, take into future. Presented with evidence that abortion, even in the first trimester, account the recent record-based studies discussed herein. Moreover, the mortality is associated with higher rates of death among women, the Supreme statistics they do rely upon are subject to all of the same criticisms described below. Court could determine that the new demonstration of facts is sufficient 6 Casey, 505 U.S. at 861-64. to establish that the State has a compelling interest in regulating or even prohibiting abortion in the first trimester. 9 While such a ruling might 7 Mika Gissler et a\., Pregnancy-Associated Deaths in Finland 1987-1994 -- Definition Problems and Benefits of Record Linkage, 76 ACT A OBSTETRICIA ET GYNECOLOGICA SCANDINA VICA 651 (1997). 9 Such an interpretation would be consistent with reasoning employed in Casey which

8 David C. Reardon et a\., Deaths Associated with Pregnancy Outcome: A noted that advances in medical knowledge required a rejection of the strict trimester Record Linkage Study of Low Income Women, 95 S. MED. 1. 834 (2002). system established in Roe. Casey, 505 U.S. at 873. Regarding the interest of the State in protecting viable unborn humans, the Court recognized that advances in fetal care had Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 3 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-3 open the way for states to enact and enforce the type of restrictions that departure from stare decisis might undermine the Court's credibility,12it existed prior to 1973, it would not require any change in constitutional is likely that the Court would overrule Roe only if its failure to do so law. Instead, such a ruling would simply apply the existing standard in would cost women, their families, and the nation, a "terrible price.,,13 Roe to the best current understanding of facts. In that event, the For abortion opponents, that "terrible price" would be the physical and principle of stare decisis would be preserved and the Court could not psychological damage women suffer from abortion, plus the loss of pre- be accused of "compromises with social and political pressures.,,10 In viable human lives, that would continue in states that might fail to short, the Court may allow new restrictions on abortion due to a adequately restrict abortion. For abortion supporters, that "terrible change in facts without engaging in any reinterpretation of price" would be the loss of easy access to abortion, as either a tool for constitutional law. self-determination or as a tool for population control, eugenics, or social Alternatively, as signaled in Planned Parenthood v. Casey, a engineering. Faced with these two opposing viewpoints, but confronted demonstration that key factual assumptions in Roe were actually false with a change in facts sufficient to reject Roe's standard as useful for might justify a complete repudiation of Roe. II However, since such a determining when the State has a compelling interest in protecting maternal health, the Court could either (a) return the task of judging the medical evidence for when abortion is contraindicated or medically resulted in a shift in viability into the second trimester, which meant that the State justified to state legislators and state regulators, thus opening the way therefore had a compelling interest in protecting viable human lives prior to the third to a hodgepodge of different regulations in different states; (b) require trimester. Id. at 859-60. Using similar reasoning, the Court might rule that Roe's other central holding -"the State may enact regulations to further the health or safety the States to prohibit abortion on the grounds of an affirmative duty to of a woman seeking an abortion," id. at 878, and the State's interest in regulating protect women's health and the lives of their pre-viable children, and abortion for this purpose is compelling "at that point that the mortality rate in abortion thereby establish a single national standard; (c) define a new, more lax approaches that in childbirth," id. at 878, 929, - provides a basis for allowing State medical standard for determining when the State's interest in protecting regulation of abortion in the fIrst trimester in light of the new evidence that the mortality rate associated with abortion, even in the fIrst trimester, exceeds that women's health is compelling; or (d) define the right to seek and associated with childbirth. perform abortions as an absolute right that is not subject to any State 14 10 regulation, an option that the Court has, in the past, firmly dismissed. Casey, 505 U.S. at 865.

II In Casey, the Court acknowledged that changes in factual understanding have necessitated the reversal of basic judicial interpretations of the Constitution in the past, with abortion, in addition to new evidence linking abortion with higher rates of physical but that the claim of such a change in facts had not been presented to the Court in and psychological morbidity, it has become clear (to paraphrase the Court's above- Casey. Id. at 861-64. In a discussion of cases when the Court had appropriately stated analysis of Lochner) that Roe rests on false factual assumptions about the overruled prior interpretations of constitutional law, the court noted, as an example, capacity of a relatively unregulated abortion industry to satisfy minimal levels that West Coast Hotel Co. v. Parrish, 300 U.S. 379 (1937), "signaled the demise of of women's welfare. Lochner" because the Depression had exposed the 12Id. at 864-69. false factual assumptions about the capacity of a relatively unregulated market to satisfy minimal levels of human welfare ... The facts upon which the earlier case 13 Id. at 864. [Lochner] had premised a constitutional resolution of social controversy had

proven to be untrue, and history's demonstration of their untruth not only justifIed 14 "Some amici argue that the woman's right is absolute and that she is entitled to but required the new choice of constitutional principle that West Coast Hotel terminate her pregnancy at whatever time, in whatever way, and for whatever reason she announced .... [T]he clear demonstration that the facts of economic life were alone chooses. With this we do not agree." Roe, 410 U.S. at 153. "The privacy right different from those previously assumed warranted the repudiation of the old law. involved, therefore, cannot be said to be absolute. . . . The Court has refused to Id. at 861-62. recognize an unlimited right of this kind in the past." Id. at 154. "Even an adult woman's right to an abortion is not unqualifIed." H.L. v. Matheson, 450 U.S. 398, 419 Similarly, in the face of growing evidence about the higher mortality rates associated (1981) (Powell and Stewart, concurring); see also Planned Parenthood v. Danforth. 428 Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 4 of 26

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While none of these options will satisfY all parties, the latter two seem previously been done. To that end, the remaining portion of this paper especially unlikely as these would require the Court to determine that a will review the basis for and the difficulties involved in prior efforts to higher priority must be placed on protecting the abortion "liberty,,15 compare the mortality rates of abortion and childbirth, examine the than on the protecting women's health. strengths and weaknesses of the new record-based studies, and examine Even if new information on abortion-associated mortality were not these findings in the light of related research that provides an additional to have any effect on the constitutional law governing abortion context in which to interpret these results. regulations, however, it should have an impact on the medical judgment of physicians recommending abortion. This is especially true in countries such as Great Britain, which only allow abortion when it is medically deemed to be safer than carrying a child to term.16 Obstacles in Assessing Pregnancy Associated Deaths Clearly, the question of the comparative mortality rates of abortion and childbirth is an important legal and medical issue. Therefore, the On March 1, 1989, Erica Richardson, a sixteen-year-old Maryland purpose of this paper is to examine the evidence accumulated resident, bled to death from a uterine perforation only hours after regarding these comparative mortality rates in greater detail than has undergoing an abortion. During the next five months, two other residents of Maryland, Gladys Estanislao and Debra Gray, also died from abortion complications.17 Surprisingly, none of these women were ever granted the smallest of recognitions-becoming a statistic. The U.S. 52, 60 (1976); Casey, 505 U.S. at 875-76. official statistics issued by Maryland public health officials showed that 15 Casey, 505 U.S. at 869. there were no deaths from abortion in 1989. Indeed, Maryland only reported a single abortion-related death for the entire decade of 1980 to 16 In the United Kingdom, the 1967 abortion act provides that an abortion is legal 1989.18 if two registered medical practitioners are of the opinion, formed in good faith - a) Actually, there was a fourth woman who died as a result of a 1989 that the continuance of the pregnancy would involve risk to the life of the pregnant abortion in Maryland. In this case, Susanne Logan fell into a coma woman, or of injury to the physical or mental health of the pregnant woman or any existing children or of her family, greater than if the pregnancy were terminated; during her abortion and awoke four months later as a quadriplegic, or b) that there is a substantial risk that if the child were born it would suffer from unable to talk. She survived for three years, dying in 1992 at the age of such physical or mental abnormalities as to be seriously handicapped. twenty- four.19 Since Susanne's death did not occur within forty-five The Public General Acts, 1967, p. 2033, (Eng.) (emphasis added); see a/so The Public days of her abortion, it has not been counted in any of the official General Acts, Human Fertilization and Embryology Act, 1990, p.1493, c.37 (Eng.) abortion mortality statistics. The Act states that the time limit is defined in terms of These four deaths occurred in one small state. For that same year, (a) that the pregnancy has not exceeded its twenty. fourth week and that the 1989, the Abortion Surveillance Unit of the Centers for Disease Control continuance of the pregnancy would involve risk, greater than if the pregnancy

were terminated, of injury to the physical or mental health of the pregnant woman 17 or any existing children of her family or (b) that the termination is necessary to Kevin Sherlock, Victims of Choice, 134-35 (1996). prevent grave permanent injury to the physical or mental health of the pregnant 18 . woman; or (c) that the continuance of the pregnancy would involve risk to the life 1d of the pregnant woman, greater than if the pregnancy were terminated; or (d) that 19 S . there is a substantial risk that if the child were born it would suffer from such HERLOCK,supra note 17, at 33; James A. Miller, 'Safe and Legal'--Back in New physical or mental abnormalities as to be seriously handicapped. York and Maryland, HLI REPORTS,Feb.1993, at 8-9; Retha Hill, 2 Tragedies Raise Doubts About Suitland Clinic: Abortion Patient, Left Paralyzed, Files Suit, WASH. Id., available at http://www.legislation.hmso.gov.uk/cgi- POST,Aug. 13, 1990, at AI; Botched-abortion Victim Dies in , WASH.TIMES, bin/search.pl?DB=hmso-new (last visited Apr. 17,2004). Dec. 2, 1992, at B2. Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 5 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-5 and Prevention (CDC) reported only twelve abortion-related deaths for In many cases, the physician filing the death certificate may not the entire country.20 But, as we will see, the CDC lacks any regular know about a recent birth unless told by relatives. The physician is and systematic means of identifying abortion-related deaths. even less likely to know about a recent abortion, since most American There are numerous inherent difficulties involved in efforts to women obtain abortions from specialists, not their own personal identify deaths related to pregnancy, childbirth, and abortion. First, it physicians. Similarly, interviews with relatives are less likely to be is obvious that the quality of analyses and conclusions can never revealing in regard to abortion than they are in regard to childbirth, or surpass the quality of data sources. Inaccurate data will produce even miscarriage. The deceased may not have told relatives about her inaccurate conclusions. abortion. Even if they are aware of it, relatives might refrain from Claims that abortion mortality rates are lower than maternal telling the physician completing the death certificate about the abortion mortality rates related to childbirth are based on comparing two sets of simply because they would not want it noted on this public record. statistics: maternal mortality rates compiled by the National Center for There is also the risk that persons involved in reporting the death may Health Statistics (NCHS) through its National Vital Statistics System, deliberately obscure the underlying cause in cases of abortion-related 21 and the number of deaths reported to be abortion related by the CDC. death. This may be done either to protect families from potential This comparison is problematic for two general reasons. First, NCHS embarrassment or to avoid the implication of malpractice against the and CDC employ different standards and means of data collection. abortion providers, who in some cases may also be the attending Second, both systems are prone to missing a large percentage of deaths physician who is completing the death certificate. associated with childbirth and abortion. Additional ambiguities arise in regard to efforts to accurately Death certificates are the primary source of data used by NCHS to identify deaths that are related to pregnancy. The International compile mortality statistics through its National Vital Statistics Classification of Diseases ninth revision (ICD-9) defined "maternal System. In the United States, cause of death on death certificates is death" as one which occurs while a woman is pregnant or within forty- normally reported by the attending physician. In some cases, two days of the termination of the pregnancy, regardless of the outcome particularly when the cause of death is due to violent or unknown (abortion, miscarriage, or delivery) and anatomical site of the causes, medical examiners or coroners will make the final pregnancy, where the death is judged to be caused by a disease related classification of causes. In either case, a recent pregnancy may not be to or aggravated by the pregnancy or its management, excluding recorded due to error or lack of knowledge on the part of the attending incidental deaths.23 The provision to exclude deaths deemed to be physician or coroner. More careful analyses in individual states reveal "incidental" introduces subjective judgments that are often reversed that fifty percent or more of death certificates for pregnant or recently upon closer review.24 For example, it is frequently unclear what role, if pregnant women failed to note the pregnancy.22 any, a current or recent pregnancy may have in deaths resulting from "some cancers, stroke, asthma, liver cirrhosis, pneumonia with influenza, anorexia nervosa, and many violent deaths such as suicide, 20 Lisa M. Koonin et aI., Abortion Surveillance.-United States, 1992,45 MORBIDITY& homicide, and accidents.,,25 MORTALITYWEEKLYREpORT1, 17 (1996). 1993-1998,285 JAMA 1455, 1455 (2001). 21 William Cates, Jr., et aI., Mortality From Abortion and Childbirth: Are the Statistics Biased?, 248 JAMA 192-96 (1982). 23 World Health Organization, The International Statistical Classification of Diseases and Related Health Problems (9" rev. 1978). 22 Timothy D. Dye et aI., Retrospective Maternal Mortality Case Ascertainment in West Virginia, 1985 to 1989, 167 AM. J. OBSTETRICS& GYNECOLOGY72,76 (1992); 24 Horan, supra note 22, at 1459. Centers for Disease Control and Prevention, Pregnancy-Related Mortality-Georgia, 1990-1992,44 MORBIDITY& MORTALITYWEEKLYREPORT81,93 (1995); Isabelle L. 25 Gissler, supra note 7, at 652. Horan et aI., Enhanced Surveillance for Pregnancy-Associated Mortality-Maryland, Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 6 of 26

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Moreover, the limitation to forty-two days after the pregnancy ectopic pregnancies are especially problematic since ectopic outcome is an arbitrary one, chosen to parallel the time period used in pregnancies are the leading cause of maternal death in the United defining infant mortality. While it is known that some deaths related States.29 to pregnancy complications may occur outside this forty-two day Another disparity in tracking deaths associated with childbirth and period, as in the case of Susanne Logan, a specific time restriction is a abortion is related to different coding standards. Coding rule 12 of the practical coding convenience. A forty-two day time limit would also ICD-9 requires that deaths due to medical and surgical treatment must distort comparisons if delayed deaths are more commonly associated be reported under the complication of the procedure (embolism, for with abortion than childbirth. More certainly, this definition of example) and not under the condition for treatment (elective abortion). maternal death associates a far larger period of time to maternal deaths According to researcher Isabelle Begin, than abortion deaths. In the case of abortion, the maximum period of In effect, this makes abortion a "ghost" category under which time covered is forty-two days. In all other cases, every death it is impossible to code a death. Medical coders have, in fact, occurring at any time during the pregnancy, plus an additional forty- relayed that any attempt to code a death due to abortion under two days, must be considered as possible maternal deaths. In other an abortion category yields a "reject message" from the words, abortion related deaths cover forty-two days of a woman's life computer programs provided by the National Center for compared to 312 days (on average) for women who carry to term. This Health Statistics of Washington D.C., a division of the U.S. seven-fold longer time period automatically encompasses a larger Centers for Disease Control in Atlanta, Georgia .... These number of deaths and greater exposure to errors in judgment regarding computer programs simply incorporate the same problematic whether or not the pregnancy was a contributing cause of death, coding rules already used throughout the world. Only a especially in cases of death due to natural causes, such as heart failure. minute number of abortion-related deaths actually qualify to To further complicate matters, if a woman undergoing an abortion be declared under abortion, Le. those for which the medical has an unidentified ectopic pregnancy that subsequently ruptures and certificate of death categorically and unequivocally gives causes her death, should that be counted as an abortion related death or abortion as the underlying cause of death. If abortion is a maternal death? The CDC researchers who compile statistics on mentioned anywhere else on the death certificate, on the abortion deaths have chosen to exclude deaths from ectopic pregnancy 26 underlying cause line, the death gets coded as an accident of following an abortion even though the deaths are at least partially due some kind, a sudden or unexpected death, an illness (like to the failure of the abortion provider to verify the site of the septicaemia-blood poisoning) or an injury, etc.30 pregnancy and the completion of the abortion.27 An additional While there are numerous three digit ICD codes for identifying confounding factor is that scar tissue resulting from a prior induced specific causes of death related to pregnancy and delivery (such as 633 abortion may be associated with increased risk of subsequent ectopic 28 for ectopic pregnancy, 640 for hemorrhage in early pregnancy, 666 for pregnancies. All of these considerations regarding abortion and

aI., Ectopic Pregnancy and Prior Induced Abortion, 72 AM. J. PUB. HEALTH253 (1982).

26 Centers for Disease Control, Abortion Surveillance (1979). 29 Kees P. Nederof et aI., Ectopic Pregnancy Surveillance, United States, 1970 - 1987, 27 Hani K. Atrash et aI., Ectopic Pregnancy Concurrent with Induced Abortion: 39 MORBIDITY& MORTALITYWEEKLY REPORT 9 (1990). Incidence and Mortality, 162 AM. 1. OBSTETRICS& GYNECOLOGY726, 729 (1990); J. M. Hardman et aI., Ectopic pregnancy association with induced abortion: message for 30 Isabelle Begin, False Abortion Statistics Exposed, REALITY (REAL Women of the pathologist, ARCHIVESPATHOLOGY& LABORATORYMED. 117,698-700 (1993). Canada, Ottawa, Ontario), Sept.-Oct. 1999, available at http://www.realwomenca.com/newsletter/1999 _Sept_Oct/article_ 28 Catherine Tharaux-Deneux et aI., Risk of Ectopic Pregnancy and Previous Induced 1O.html (last visited Apr. 17,2004). Abortion, 88 AM. J. PUB. HEALTH401 (1998); See generally Ann Aschengrau Levin et Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 7 of 26 <"

Deaths Associated with Abortion Compared to Childbirth--A Review page-7

postpartum hemorrhage, et cetera), there is only one code for legally implemented, the CDC identified twice the number of abortion related induced abortion (635), and it is chiefly intended to identify when an deaths as those reported by NCHS,34 while in the 1980s it discovered abortion was provided in medical and billing records. As described only three percent more abortion related deaths than NCHS. By above, the code for a legally induced abortion is not intended for use contrast, a single investigative journalist examining public records, when identifying cause of death. Examination of death certificates including autopsies and malpractice suits, documented thirty to thirty- where abortion is known to be the underlying cause of death reveals nine percent more abortion related deaths than were reported by either that code 635 (legal abortion) is rarely identified as the cause of NCHS or the CDC.35 death.3' In short, death certificates are not a reliable source for identifying deaths related to childbirth and are an even weaker means of How Accurate is the CDC Surveillance System? identifying deaths related to abortion. In 1972, Family Planning Evaluations Division of the CDC implemented a patchwork method for In the years following legalization of abortion, the CDC's efforts to identifying abortion related deaths to "complement the vital statistics investigate abortion-related deaths and complications were led by vocal proponents of abortion, some of whom also performed abortions in their activities of NCHS by identifying causes of preventable abortion 36 deaths.',32 We describe this surveillance system as a "patchwork private practices. As a result, opponents of abortion questioned the system" because it does not rely on any regular source of data. Since CDC's commitment to fully identify and document abortion-related injuries. More specifically, it was charged that the CDC reports no state has laws or regulations requiring doctors, emergency room 37 personnel, or coroners to report possible abortion related deaths for regarding abortion-related deaths were misleading. investigation, the CDC system simply investigates such deaths if they In response to concerns raised about the completeness of their happen to come to their attention through "reports from state health statistics on abortion- related deaths, CDC investigators responded with departments, case histories published in medical journals, anecdotal a paper published in one of the country's premier medical journals, reports from state medical or hospital associations, CDC special JAMA, in which they state, "Although it is likely that the CDC has not surveys of deaths from other fertility control measures, reports to identified all abortion deaths in the United States since 1972, every national abortion organizations, registries from the Food and Drug reported death has been counted in CDC statistics.',38 The real question, Administration, and reports from state maternal mortality review however, is how many abortion related deaths are not reported? In committees. ,,33 response to this question, the CDC team offered a statistical analysis The inadequacy of this system of reliance on ad hoc tips is based on "the Chandrasekaran-Deming theory" [sic] as evidence that illustrated by the fact that for the period immediately after it was

31 See generally SHERLOCK,supra note 17. According to one assessment by the 34Id. Centers for Disease Control, NCHS data identified only thirty percent of the abortion- 35 related deaths that CDC identified through its follow-up system, which also has many SHERLOCK,supra note 17, at 117. weaknesses as described elsewhere in this paper. See William Cates, Jr., et al., 36 Assessment of Surveillance and Vital Statistics Data for Monitoring Abortion Mark Crutcher, Lime 5 146 (1996). Mortality, United States, 1972-1975, 108 AM. 1. EPIDEMIOLOGY200,201 (1978). See also Cates, Jr., et al., supra note 21, at 192-6. . 37 Thomas W. Hilgers, M.D., & Dennis O'Hare, Abortion Related Maternal Mortality:

32 An In-Depth Analysis, in NEWPERSPECTIVESONHUMANABORTION69, 70 (Thomas W. Cates, Jr., et aL, supra note 31, at 201. Hilgers et aL eds., 1981).

33 . Id 38 Cates, Jr., et aL, supra note 21, at 193 (emphasis added). Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 8 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-8 they were successfully tracking "90% of all abortion deaths.,,39 only twenty-seven.44 This claim, and the statistical analysis on which it was based, Third, the Sekar-Deming theory makes no allowances for deliberate deserves detailed examination. While the research articles published deception, which critics insist is the primary cause for the by investigators within CDC's Family Planning Evaluation Division underreporting of abortion-related deaths. The Sekar-Deming method is consistently reflected a favorable opinion of abortion, the egregious applicable only for relatively neutral data which might be missed by one misapplication of statistical methods in this particular study strongly surveillance system or another merely because of clerical errors, lost suggests that their analyses were being used to deliberately promote an forms, changes of address, et cetera.45 unjustified confidence in abortion safety. Perhaps the best way to demonstrate why the Sekar-Deming formula Specifically, the CDC researchers used "the cannot be appropriately applied to surveys of abortion deaths is to Chandrasekaran- Deming theory" [sic] that "compares the results of examine the type of analysis it was developed to do. The statistical two independent systems of ascertaining the same event and provides method developed by Sekar-Deming was originally designed to provide an estimate of the completeness of ascertainment in both systems," to a method of checking the accuracy of birth and death registration in compare the abortion death tallies generated by NCHS and the data underdeveloped provinces of India. They specifically wanted to know 40 collected by CDC. The wrongly cited statistical theory used was what percent of deaths and births were not being recorded in the official actually that of C. Chandra Sekar and W. Edwards Deming and birth and death registries. Their statistical method compared the reference to the original paper reveals strict limitations upon its "official" records to a list obtained from house-to-house canvass 41 application. All of these restrictions were violated by the CDC surveys in small test areas. Note that this was a literal house-to-house analysts. survey looking for common events, births and deaths, during the past First, the Sekar-Deming theory applies only to a comparison of year.46 Neither the NCHS nor the CDC surveillance systems are nearly independent surveys.42 NCHS and CDC data, however, are heavily as thorough as this. If the CDC had a list of all women who had aborted interdependent since the CDC uses state health agency reports in the in the U.S. and called on each home to find out if the woman had died same way as the NCHS. At best, NCHS statistics are merely a subset from her abortion, only then would it approach the independent survey of CDC data, not an "independent" study.. status envisioned by Sekar and Deming. Instead, toe CDC begins its Second, the theory is valid only "over an area large enough to tally by using the NCHS report and supplements this with reports from contain a large number ofN events.,,43 But even the severest critics of physicians and other authorities - the same people who should have abortion do not believe that abortion-related deaths are statistically "a been responsible for correctly reporting abortion-related deaths to the large number" of events compared to the total number of abortions NCHS through death certificates.47 In other words, the CDC simply performed. The most deaths reported to the CDC in anyone year were draws on the same group of information suppliers who should have correctly reported the abortion deaths the first time. This lack of independently derived data is in very sharp contrast to the 39 . Id Sekar-Deming population study that compared the statistical reports of 40 Cates, Jr., et aI., supra note 31, at 201.

41 44 C. Chandra Sekar & W. Edwards Deming, On a Method of Estimating Birth and Cates, Jr., et aI., supra note 21, at 193. Death Rates and the Extent of Registration, 44 1. AM. STAT. Ass'N 101, 102 (1949). Note: The authors' names were cited incorrectly by the CDC authors. 45 Sekar & Deming, supra note 41, at 102.

42 fd. at 102.; Cates, Jr., et aI., supra note 31, at 201. 46Id.

47 43 Sekar & Deming, supra note 41, at 103 (emphasis added). Cates, Jr., at aI., supra note 31, at 201. Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 9 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-9 village officials (data gathering officials analogous to physicians and politician's spin on the news to promote a partisan agenda. An health agencies) with a survey of the general populace who would be objective evaluation of the CDC report in the direct light of a more intimately aware of the events in question (a group analogous to comparison to the conditions required for application of the Sekar- aborted women and their families). Deming methodology demonstrates that the authors were either Perhaps even more importantly, the Sekar-Deming method was consciously or subconsciously unwilling to consider that induced only intended to estimate the rate of "missed events" which are abortion could be as or more dangerous than childbirth. Regardless of extremely common, Le., births and deaths in India, involving hundreds the cause for these exaggerated claims, the CDC's misapplication of the of thousands of cases or more. As Sekar's and Deming's conditions Sekar-Deming analysis is sufficient to raise concerns about the for use of the theory underscore, it is simply not appropriate to load reliability of everything the CDC has done in regard to "abortion small numbers into statistical equations designed for "meganumbers." surveillance.,,52 This concern in turn underscores the importance of Since both abortion and pregnancy-related deaths are uncommon in the record-based studies that examine deaths associated with abortion and general population, the Sekar-Deming theory cannot be appropriately childbirth using a single uniform standard. applied to an analysis of pregnancy-related death. The CDC's use of this analytic technique with such small numbers is analogous to loading a marble into a cannon. While a cannon may be relatively General Findings Using An Objective Standard accurate when launching a properly sized cannon ball, its accuracy is reduced to nil when it is loaded with a single marble. To partially address some of the difficulties described earlier with Clearly, the CDC authors violated all the conditions required to accurately identifying deaths associated with pregnancy, the tenth properly use the Sekar-Deming formula. Yet they barely give any revision of the rCD added two additional definitions for tracking notice to the possibility that their estimate may be low to the extent mortality.53 The first was "pregnancy-related death" which includes all that the "independent assessmenr' is imperfect.48 Instead, they argue deaths within forty-two days of pregnancy outcome irrespective of that if there is any error in their estimate, it is most likely that their whether the death may be incidental. The second was a definition for "strict matching criteria" and tolerance of "false positives" would lead "late maternal death," which requires exclusion of incidental deaths in to an overestimation of the number of abortion deaths.49 In other the same manner as defined for maternal deaths, but includes deaths words, they assert that "the Chandrasekaran-Deming theory" indicates after forty-two days and less than one year after the pregnancy outcome. that they are identifying ninety-four percent of all abortion related Still another classification, "pregnancy-associated death," has been deaths, but they are probably doing even better than thaeo proposed by the CDC and the American College of Obstetricians and The degree to which the authors stretched to promote confidence in Gynecologists (ACOG), which encompasses features of both their weak "surveillance system,,51arouses suspicions of bias. Even the pregnancy-related deaths and later maternal deaths by including all tone used to bolster confidence in their results is reminiscent of a deaths within one year of pregnancy outcome, irrespective of cause of corporate report designed to instill confidence among investors or a death or the anatomical site of pregnancy.54 This latter definition

52 CRUTCHER, note 36, at 135-70. 48 [d. at 204. supra

S3 World Health Organization, The International Statistical Classification of Diseases 49 [d. at 203-04. and Related Health Problems (10th rev. 1992).

50 [d. at 203. S4 Hani K Atrash et al., Maternal and Perinatal Mortality, 4 CURRENTOPINIONIN 51 [d. at 201; Cates, Jr., et al., supra note 21, at 193. OBSTETRICS& GYNECOLOGY61, 62 (1992). Yet another proposal has been made to measure the "reproductive mortality rate," which would include deaths from Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 10 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-lO significantly reduces the chance that deaths will be missed because making a direct comparison of women who deliver to women who have they fall outside the forty-two day window and eliminates the inherent abortions. In this study, compared to Finnish women who delivered, the problems involved in subjective judgments about causality. age-adjusted odds ratio of dying in the year following an induced Because the definitions for both pregnancy-related death and abortion was 1.63 for deaths from natural causes, 4.24 for deaths from pregnancy-associated death eliminate the effects of subjective errors, injuries related to accidents, 6.46 for deaths resulting from suicide, and these new criteria are much better suited for large record-based studies 13.97 for deaths resulting from homicide.57 which link death certificates to medical records for pregnancy, The second record-based study to compare deaths following abortion childbirth, and abortion. Only two such studies have been published, and childbirth linked Medicaid records for 173,279 California women but both show with high statistical reliability that abortion is associated who had state-funded abortions or deliveries in 1989 to death with elevated mortality rates compar:edto childbirth. certificates from 1989 to 1997.58 Approximately thirty percent of all The first of these was a national study of all women aged fifteen to abortions and deliveries in California in 1989 were funded by Medicaid. 55 forty-nine in Finland who died from 1987 to 1994. Death certificate While the findings of this study paralleled the general findings in identifiers were linked to the birth, abortion, and hospital registries to Finland, this study is particularly significant in that it demonstrated (1) identify if the women had been pregnant during the last year of their that the elevated risk of death associated with abortion persists beyond lives. Because Finland has socialized medicine and a computerized one year; (2) the elevated risk of death following an abortion is not central registry, the completeness of these records and quality of explained by prior psychiatric history, at least during the year preceding linkage is excellent. The researchers found that women who carried a the target pregnancy; and (3) subsequent pregnancy events, for example pregnancy to term were half as likely to die in the year following their a delivery following abortion, may significantly reduce the elevated pregnancy as are women who were not recently pregnant (Odds Ratio mortality rate associated with an abortion. Controlling for age and = 0.50; 95% Confidence Interval = 0.32 to 0.78). The reduced risk of psychiatric history, aborting women were sixty-one percent more likely dying held true across all major categories: natural causes, suicide, to die from all causes over the eight years examined (OR = 1.61; 95% accidents, and homicide. Women who had an induced abortion, by CI = 1.30 to 1.99), seventy-eight percent more likely to die of violent contrast, were significantly more likely to die than non-pregnant causes (OR = 1.78; 95% CI = 1.28 to 2.47), and forty-four percent more women (OR = 1.76; 95% CI = 1.27 to 2.42).56 likely to die of natural causes (OR = 1.44; 95% CI = 1.08 to 1.91), and This comparison to mortality rates for women who had not been there is less than one-in-a-thousand chance that these findings are due to recently pregnant suggests that the disparity in death rates between chance (p < .001).59 Projected to the national population of women delivering and aborting women may reflect two active effects: (1) having abortions, these findings would suggest that there are between giving birth may have a protective effect, and (2) having an abortion 2,132 and 7,036 excess deaths per year among women with a history of may have a deleterious effect. Both effects are captured by means of abortion.60 complications of contraception as well as those from pregnancy, delivery, and abortion. This even broader definition has been proposed since deaths from 57 ld. at 253. The odds ratios reported here are derived from the results reported in contraception complications now appear to be more common than deaths from Table 3 by dividing the age-adjusted odds ratio reported for abortion by the age-adjusted childbirth. See Benjamin P. Sachs et aI., Reproductive Mortality in the United States, odds ratio reported for childbirth. 247 JAMA 2789 (1992); Maternal Morality Committee, I.MA. Maternal Morality 58 Reardon, supra note 8, at 834. Committee Report 1981, 75 IRISHMED.J. 484 (1982).

59 ld. at 838 tb1.3. 55 Gissler, supra note 7, at 652.

56 60 This estimate is based on a projection of the low and high odds ratios determined by 1d. the ninety-five percent confidence interval (1.30 to 1.99) reported in Table 3, id., to an Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 11 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-II

The Finland and California studies complement each other, with the and wars combined.61 Over the eight-year period examined with the strengths of one study counterbalancing the weaknesses of the other. population of Medicaid eligible women in California, after controlling For example, the Finland study was a national study that included all for age and psychiatric history, aborting women were 3.1 times more Finnish women, a racially homogeneous population, whereas the likely to die from suicide compared to delivering women.62 In the population in the California study was racially diverse. Similarly, Finland study, as shown in Figure 1, women who had abortions were while the California sample was restricted to low income women, the 3.7 times more likely to die from suicide in the year following abortion Finland sample included women of all socioeconomic groups. While than non-pregnant women and 6.5 times more likely to commit suicide the analysis of Finnish women was restricted to one year, the analysis than women who had given birth.63 Two of these suicides were also of California women showed the effects over a period of years. For connected with homicides. Examples of post-abortive women killing example, the elevated risk of death from violent causes following an their born children in concert with a suicide attempt following an abortion appears to decline rapidly over a four-year period. The abortion have also been documented in the United States.64 complementary nature of the two studies indicates that the higher mortality rates associated with abortion compared to childbirth are not explained by age, race, socioeconomic status, or psychiatric history. In 61 World Health Organization, World Report on Violence and Health (Etienne G. Krug the sections that follow, the findings of these two studies in regard to et al. eds., 2002) at 10 tbl.1.2. 62 specific causes of death will be examined in the context of related Reardon, supra note 8, at 838. literature on abortion and childbirth that sheds light on the 63 G' I interpretation of these results. ISS er, supra note 7, at 653.

64 Clinicians who specialize in post-abortion counseling have reported case studies in which traumatic reenactment of a past abortion has been manifested by intrusive thoughts of hurting a woman's other children. THERESAK. BURKE & DAVID C. A Closer Look at Differences in Rates of Death from Suicide REARDON,FORBIDDENGRIEF:THEUNSPOKENPAINOFABORTION182-85 (2002). One week after Donna Fleming's second abortion, Donna was depressed and Worldwide, suicide accounts for nearly as many deaths as homicide distraught and began to "hear voices." With the hope of reuniting herself and her two living sons with her aborted children, she jumped off a bridge in Long Beach California with her five-year-old and two-year-old sons in her arms. Donna and her five-year-old son were rescued; her two-year-old died. A. McFadden, The Link Between Abortion and estimated 1.4 million women having abortions each year. It also assumes the base rate Child Abuse, FAMILYRESOURCESCENTERNEWS,January 1998, at 20. of 507.7 deaths per 100,000 for all causes of death over an eight-year follow-up period also reported in Table 3. Sandi Nieves was convicted of setting a fire in the kitchen of her home where she and her five children slept, which led to the death from smoke inhalation of four of her Another way to measure the potential cost of higher death rates is in terms of woman- daughters. Nieves and her son survived the apparent suicide/homicide attempt. Nieves years. If the average life expectancy of a woman is around seventy-six, and the had been taking antidepressent drugs to cope with her abortion that occurred just five average age at time of death among the excess number of deaths associated with days before the fire. Caitlin Liu, Mother Breaks Down in Tears at Murder Trial, L.A. abortion is twenty-eight, this translates to forty-eight woman-years lost per death. In TIMES,June 20, 2000, at B3. the one-year follow-up study by Gissler (supra note 7), compared to delivering women there were 73.8 extra deaths per 100,000 for women who had abortions. Multiplied by Renee Nicely of New Jersey experienced a "psychotic episode" the day after her forty-eight woman-years lost, this equals 3542 woman-years per 100,000 abortions. abortion that resulted in the beating death of her three-year-old son, Shawn. She told the Projected onto the entire population of approximately thirty million American women court psychiatrist that she "knew that abortion was wrong" and "I should be punished who have had abortions, this represents a potential loss of 1.1 million woman-years. for the abortion." The psychiatrist who was the prosecution's expert witness testified Applying the same formula to the excess deaths identified in the eight-year period that the killing was clearly related to Renee's psychological reaction to her abortion. examined by Reardon, supra note 8, the same method and assumptions would produce Debra Braun, Woman Kills 3-Year-Old Son One Day After Obtaining Abortion, NAT'L. an estimated loss of 14,400 woman-years per 100,000 abortions. RIGHTTOLIFENEWS,Oct.B, 1983, at 12. Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 12 of 26

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Notably, the risk of suicide following a birth was about half that of the general population of Finnish women. This finding is consistent Figure 1 with previous studies that have shown that an undisturbed pregnancy is associated with a reduced risk of suicide.65 A fifteen-year study of nearly one million women has also shown that the number of children Death by Suicide a woman has is strongly and inversely related to the relative risk of suicide.66 Other research has shown that a greater sense of family 4 obligation and a fear of hurting one's children are associated with 67 fewer suicide attempts and suicidal thoughts. In one study of women 3 with a prior history of psychiatric problems, none of those who carried to term subsequently committed suicide over an eight-to-thirteen-year follow-up, while five percent of those who aborted subsequently 2 committed suicide.68 These findings suggest that for women with prior psychological problems, childbirth is likely to reduce the risk of 1 subsequent suicide attempts. By contrast, women with prior psychiatric illness appear to have higher suicide rates following their abortions.69 This suggests that o abortion may aggravate prior psychological illness and precipitate No Pregnancy Birth Miscarriage Abortion suicidal thoughts. Some have therefore proposed that the higher rate of suicide among aborting women may be completely explained by To investigate this theory, researchers at the South Glamorgan psychological differences between aborting and delivering women. Health Authority in Great Britain (population 408,000) reviewed Risk-taking and self-destructive women, for example, may be more records on admissions for suicide attempts both before and after likely to become pregnant and have abortions than "normal" women. pregnancy events.70 Among the women who aborted, researchers identified a shift from a roughly "normal" suicide attempt rate before 65 See Louis Appleby, Suicide During Pregnancy and in thePirst Postnatal Year, 302 the abortion to a significantly higher suicide attempt rate after the BRIT. MED. J. 137 (1991); Sandra J. Drower & Eleanor S. Nash, Therapeutic Abortion abortion. In the post-pregnancy period, there were 8.1 suicide attempts on Psychiatric Grounds: Part 1. A Local Study, 54 SOUTH AFRICAN MED. J. 604 per thousand among those who had abortions compared to only 1.9 (1978); Bengt Jansson, Mental Disorders After Abortion, 41 ACTA PSYCHIATRICA suicide attempts per thousand among those who had given birth.71 The SCANDINAVIA87 (1965); Louis Appleby & Gill Turnbull, Parasuicide in the First higher rate of suicide attempts subsequent to abortion was particularly Postnatal Year, 25 PSYCHOL.MED. 1087 (1995). evident among women under thirty years of age. The results of their 66 Georg Hoyer & Eiliv Lund, Suicide Among Women Related to Number o/Children analyses are even more striking when viewed graphically. Figure 2 in Marriage, 50 ARCHIVESGEN. PSYCHIATRY134, 137 (1993). shows that the attempted suicide rates, by age group, remained relatively flat or declined before and after pregnancies that resulted in 67 Marsho M. Linehan et aI., Reasons for Staying Alive When You Are Thinking About Killing Yourself: The Reasons for Living Inventory, 51 J. COUNSELING & deliveries. CLINICALPSYCHOL. 276 (1983).

68 Jansson, supra note 65, at 87. 70 Christopher Morgan et aI., Suicides After Pregnancy: Mental Health May Deteriorate as a Direct Effect of Induced Abortion, 314 BRIT. MED. J. 902 (1997). 69 Esther R. Greenglass, Therapeutic Abortion and Psychiatric Disturbance in 71 . Canadian Women, 27 CANADIANPSYCHIATRICASS'N 1. 453 (1976). Id Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 13 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-13

By contrast, the attempted suicide rates before and after controlled for psychiatric history.73 This suggests that prior psychiatric pregnancies ending in abortion rose significantly for each age group illness may play a bigger role in suicides following childbirth than it (Figure 3). These findings disprove the hypothesis that suicidal does in cases of suicide following abortion.74 While it does not appear women are more likely to become pregnant and choose an abortion. that prior psychological history can fully explain the higher suicide rates Instead, the researchers concluded, these findings indicate that "the associated with abortion, it is also true that an abortion may aggravate increased risk of suicide after an induced abortion may therefore be a pre-existing psychological disturbances and place this subgroup of consequence of the procedure itself."n aborting women at a higher risk of suicide. Figure 2 Figure 3

Rate of attempted suicides per 1000 by age group before and after Rate of attempted suicides per 1000 by age group before and delivery after abortion

16TI------, 14 14 .LI _ 12 ...- ...-- 12 10

10 ---15-19 - __ 15_19 - - 20-24 - - 20.24 - - - - 25-29 - - - - 25.29 6

4 4-1:--- _ --- 2 ...... -_ ...... •.. ------_ .. o Before Abortion Afier Abortion Before Delivery A 1ter 0 elivery

The above interpretation of record-based studies and case-control The hypothesis that differences in prior psychological illness studies is strongly supported by reports of clinicians and self-reports of account for the differences in suicide rates among aborting and post-abortive women. A number of published case studies have drawn a delivering women is also contradicted by the analysis of suicide deaths direct correlation befween abortion and subsequent suicides or among low-income women in California. This study revealed that the attempted suicides.75 In some cases, the attempted or completed relative risk for suicide among aborting women compared to delivering women actually increased from 2.54 to 3.12 when cases were 73 Reardon, supra note 8, at 838.

74 fd. at 836. 72 Id. 75 See general1y E. Joanne Angelo, Psychiatric Sequelae of Abortion: The Many Faces Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 14 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-14 suicides coincide with the anniversary date of the abortion or expected Teens are generally at higher risk for both suicide and abortion. In a 76 due date of the aborted child. Questionnaire- and interview-based survey of teenaged girls, researchers at the University of Minnesota studies have consistently shown extraordinarily high levels of suicidal found that the rate of attempted suicide in the six months prior to the ideation (thirty to fifty-five percent) and reports of suicide attempts study increased tenfold - from 0.4 percent for girls who had not (seven to thirty percent) among women who have had an abortion.77 In aborted during that time period to four percent for teens who had many of these studies, the women interviewed have explicitly aborted in the previous six months.so described the abortion as the underlying cause of their suicidal It is also worth noting the suicide rate among women in China is the 7s impulses. Suicide attempts among male partners following abortion highest in the world. Indeed, fifty-six percent of all female suicides S1 have also been reported. 79 occur in China, mostly among young rural women. It is also the only country where more women die from suicide than men.S2 Thirty-one of Post-Abortion Grief, 59 LINACREQ. 69 (1992). See also David A. Grimes, Second- percent of all deaths among rural women between fifteen and thirty-four s3 Trimester Abortions in the United States, 16 FAM.PLAN.PERS.260 (1984); Myre Sim years of age are the result of suicide. The extraordinarily high rate of & Robert Neisser, Post-Abortive Psychoses: A Report from Two Centers, in THE suicide among Chinese women may be partially explained by China's PSYCHOLOGICALASPECTSOF ABORTION(David Mall & Walter F. Watts eds. 1979); unique "one child" family planning policy that forbids women from ANNESPECKHARD,THEPSYCHO-SOCIALSTRESSFOLLOWINGABORTION(1987). having all the children they desire, requires government permission to 76 Carl L.Tischler, Adolescent Suicide Attempts Following Elective Abortion: A Special Case of Anniversary Reaction, 68 PEDIATRICS670,670-71 (1981). 77 September 10, 2002, shot himself in the head in front of the Planned Parenthood clinic BURKE& REARDON,supra note 64, at 298; SPECKHARD,supra note 75, at 56. in Overland Park, Kansas. The suicide occurred on the first anniversary of the abortion. Three months earlier, Draper published an obituary to his aborted son in the community 78 One of many examples of women describing their suicidal impulses due to an paper that read, "Zachary Duncan Draper was beautiful as his mother, loved by God and abortion is that of Jane writing twelve months after her abortion: others. My little baby boy didn't make it to his Daddy's arms. I never got to hold and And I just have no words to describe what I went through when I woke up from the kiss him, tell him stories or read him rhymes. I love you Zachary and look forward to anaesthetic. I cry as I write this. I wanted to slice myself up, to get a gun and blow my seeing you in heaven." Kyle J. Cox, Abortion Touches Us All, TELEGRAPHHERALD, head off. I wanted to do something violent and bloody to myself - I wanted to Nov. 18, 2002, at A4. Several case studies of eighteen-to-twenty-two-year-old males literally blow myself apart. How could I have agreed to an abortion? How did I let who became suicidal following news of their girlfriends' or wives' abortions are found that happen? I ask myself those questions every day. \ in JC Dubouis-bonnefond & JR Galle-tessonneau, Psychological aspects of voluntary induced abortion amongfathers drafted into military service, 14 PSYCHOL.MED. (Paris) I did not feel I deserved to live. All I thought about was how I would kill myself, 1187-89 (1982), available at when I would kill myself. I wrote goodbye letters to my family, my good friend, and my f1atmate and researched the most efficient and effective way to kill myself - I http://www .ncbi.nlm .nih.gov /entrez/q uery .fcgi ?cmd=Retrieve&db wasn't going to make any mistakes. Afterall, ifI can kill my baby, I can sure as hell =PubMed&list_uids=12268237&dopt=Abstract (last visited Apr. 17, kill myself - and I deserve it. Because I couldn't even look after my baby when it was 2004); see also Angelo, supra note 75, at 76. right there deep inside of me. Couldn't even do that. 80 B. Garfinkel et aI., Stress, Depression and Suicide: A Study of Adolescents in Ifmy mother hadn't been going on a trip to Antarctica, which I knew meant the world Minnesota (University of Minnesota Extension Service 1986). to her, I would have killed myself. I am quite sure of this. But I thought I would wait until after her trip. IfI killed myself beforehand she wouldn't go.... The abortion has 81 Elizabeth Rosenthal, Women's Suicides Reveal China's Bitter Roots: Nation Starts to blown my life apart, blown my entire self/psyche/soul/belief in myself apart. It has Confront World's Highest Rate, N.Y. TIMES,Jan. 24, 1999, at AI. devastated me and I don't know how long this goes on for. 82Id. Melinda Tankard Reist, Giving Sorrow Words: Women's Stories of Grief After Abortion 53-55 (2000). See also Burke & Reardon, supra note 64, at 39, 172-76. 83 Michael R. Phillips et aI., Suicide Rates in China, 1995-99,359 THELANCET835,836 (2002). 79 One of the most recent examples was the suicide of Brad Draper, 44, who on Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 15 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-I5 become pregnant, and involves coerced abortions when women funded abortions had sixty-two percent more subsequent q1ental health become pregnant without a Iicense.84 claims (resulting in forty-three percent higher costs) and twelve percent more claims for treatments related to accidents (resulting in fifty-two A Closer Look at the Difference in Rates for Accidental percent higher costs) compared to a case-matched sample of women covered by Medicaid who had not had a state-funded abortion.88 Deaths Figure 4 In the Finland study, researchers found that the risk of death from accidents was more than four times higher for women who had aborted in the year prior to their deaths than for women who had carried to Death by Accidents term (Figure 4).85 Once again, giving birth appeared to have a 2.5 protective effect compared to the general population of women who had not been pregnant. In the analysis of California women, women who had an abortion in 1989 and no known subsequent pregnancies were eighty-two percent more likely to die from accidental injuries 2 during the eight years examined compared to women who delivered and had no subsequent pregnancies.86 One explanation for these findings is that women with newborn 1.5 children are more careful to avoid risks which could endanger them or their children. Conversely, women who have had an abortion may become more prone to taking risks that could endanger their lives. This data is consistent with at least two other studies that have found that women who abort are more likely to be treated for accident-related injuries in the year following their abortions. 0.5 In a study of government-funded medical programs in Canada, researchers found that women who had undergone an abortion in the previous year were treated for mental disorders forty-one percent more often than postpartum women, and twenty-five percent more often for o 87 No Pregnancy injuries or conditions resulting from violence. Similarly, a study of Birth Miscarriage Abortion Medicaid payments in Virginia found that women who had state- It is quite likely that some ofthe deaths classified as accidental in the Finland and California studies may actually have been suicides. 84 Reports of post-abortive women deliberately crashing their automobiles, David C. Reardon, Suicide Rates in China, 359 THE LANCET 2274,2274-75 (2002). often in a drunken state, in an attempt to kill themselves have been 85 Gissler, supra note 7, at 653.

86 Reardon, supra note 8, at 838 tbl.3. 88 Jeff Nelson, Interagency Memorandum, Virginia Department of Medical Assistance 87R.F. Badgley et a\., Report of the Committee on the Operation of the Abortion Law, Services regarding Data Request from Delegate Marshall (Mar. 21, 1997) (source on file Government of Canada, Minister of Supply and Services 319 (1977). with the author). Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 16 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-16 reported by post-abortion counselors and in the published literature.89 which tend to increase a woman's risk of fatal accidents. A recent study Many of these accidental deaths may result from heightened risk- of a random sample of approximately 700 women found that among taking behavior among post-abortive women that is related to women without a prior history of substance abuse, the relative risk of increased self-punishment or decreased concern for self-protection. substance abuse was 4.5 times higher subsequent to a first pregnancy Alternatively, some post-abortive women may use the adrenalin rush among women who aborted their first pregnancy compared to women that accompanies risk-taking behavior to escape a general state of who carried to term.93 A causal connection between abortion and . 90 depresslOn. subsequent substance abuse is supported by evidence from structured Elevated rates of substance abuse may also play a role in the interviews and clinical assessments of women reporting stress after an increased risk of death from accidents following abortion. Numerous abortion.94 studies have found a strong association between abortion and higher rates of subsequent alcohol consumption91 and drug abuse/2 both of A Closer Look at the Difference in Rates for Deaths from

89 Tischler, supra note 76, at 670 -71; Angelo, supra note 75; BURKE & REARDON, Homicide supra note 64, at 140, 170, 184.

90 Finland's record linkage study found homicide accounted for five Joel Osler Brende, Post-Trauma Sequelae Following Abortion and Other Traumatic percent of pregnancy-associated deaths between 1987 and 1994.95 Most Events, 7 ASSOCIATION FOR INTERDISCIPLINARYRESEARCH IN VALUES AND SOCIAL CHANGENEWSLETTER 1-8 (1994) (subsequently renamed the RESEARCHBULLETIN). of these deaths occurred among women who had undergone an abortion. As shown in Figure 5, the risk of dying from homicide for post-abortive 91 Elizabeth R. Morrissey & Marc A. Schuckit, Stressful Life Events and Alcohol women was more than four times greater than the risk of homicide Problems Among Women Seen At a Detoxication Center, 39 1. STUD. ALCOHOL 1559, among the general population. Over the eight-year period examined in 1567, 1570 (1978); Richard W. Wilsnack et aI., Women's Drinking and Drinking Problems: Patterns from a 1981 National Survey, 74 AM. J. PUB. HEALTH 1231 (1984); the mortality study of Medicaid eligible women in California, after Albert D. Klassen & Sharon C. Wilsnack, Sexual Experience and Drinking Among controlling for age and psychiatric history, homicide deaths among Women in a U.S. National Survey, 15 ARCHIVESSEXUALBEHAV. 363 (1986). Both of the preceding two studies report on a national survey which found that the percentage of women who admitted a history of abortion was significantly higher among women Pregnancy: Prevalence and Correlates, 82 PEDIATRICS 888 (1988). K. Graham & G. identified as being heavy (13%) or moderate (13%) drinkers than among light drinkers Koren, Characteristics of Pregnant Women Exposed to Cocaine in Toronto between (5%) or abstainers (4%). See Wilsnack et aI., supra; see Klassen & Wilsnack, supra. 1985 and 1990, 144 CANADIANMED. ASS'N J. 563 (1991). See generally Coleman et aI., See Tommijean Thomas et aI., Psychosocial Characteristics of Psychiatric Inpatients supra note 91. With Reproductive Losses, 7 J. HEALTH CARE FORTHE POOR & UNDERSERVED15, 18 93 David C. Reardon & Philip G. Ney, Abortion and Subsequent Substance Abuse, 26 (1996); Drower & Nash, supra note 65, tbl.VII; Priscilla K. Coleman et aI., History of AM. J. DRUG & ALCOHOLABUSE 61, 68 (2000). Induced Abortion in Relation to Substance Use During Pregnancies Carried to Term, 187 AM. J. OBSTETRICS & GYNECOLOGY 1673 (2002); J. Kuzma, & D. Kissinger, 94 Brenda Major et aI., Personal Resilience, Cognitive Appraisals. and Coping: An Patterns of Alcohol and Cigarette Use in Pregnancy, 3 NEUROBEHAVIORAL Integrative Model of Adjustment to Abortion, 74 J. PERS. Soc. PSYCHOL. 735 (1998) TOXICOLOGY& TERATOLOGY211 (1981). (self-assessment research shows that at least a minority of women report that they used drugs and alcohol as a means to cope with their feelings about the abortion); see also 92 Louis G. Keith et aI., Substance Abuse in Pregnant Women: Recent Experience at BURKE & REARDON, supra note 64, at 167-72; CANDACEDE PUY & DANA DOVITCH, THE the Perinatal Center for Chemical Dependence of Northwestern Memorial Hospital, 73 HEALING CHOICE: YOUR GUIDE TO EMOTIONALRECOVERYAFTER AN ABORTION 57, 130 OBSTETRICS GYNECOLOGY 715, 717 (1989); Thomas et aI., supra note 91, at 15-23; (1997); JEANETTE VOUGHT, POST-ABORTION TRAUMA: 9 STEPS TO RECOVERY 111-12 Drower & Nash, supra note 65, at 604-8; Hortensia Amaro et aI., Drug Use Among (1991). Adolescent Mothers: Profile of Risk, 84 PEDIATRICS 144, 147 (1989); Oro & Dixon, Prenatal Cocaine and Methamphetamine Exposure: Maternal and Neo-Natal 95 Gissler, supra note 7, at 654 tbl.III Correlates, III PEDIATRICS571 (1987); Deborah A. Frank et aI., Cocaine Use During Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 17 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-I7 aborting women were ninety-three percent higher (OR = 1.93, 95% CI naturally recede simply because the woman submits to the unwanted = 1.11 to 3.33).96 These findings are consistent with another study of abortion. Negative post-abortion reactions may instead make matters pregnancy-associated deaths in Maryland that showed that homicide is worse. the leading cause of pregnancy-associated deaths.97 Figure 5 Further investigation is necessary to more fully understand the association between abortion and increased risk of death from homicide. Increased risk-taking and substance abuse may play some role in this association, but it is also possible that many of these deaths Death by Homicide are related to domestic violence. Women who become pregnant in a violent or potentially violent domestic situation may choose abortion to 5 prevent a child from being born into an abusive situation. If this abortion is secretly obtained against an abusive male's wishes, subsequent discovery or disclosure of the abortion may result in 4 violence and even death. Alternatively, if an abusive male partner is unwilling to accept or tolerate the birth of a child, the woman may become a victim of verbal or physical abuse aimed at compelling her 3 to submit to an unwanted abortion.98 According to one study of battered women, the target of battery during their pregnancies shifted from their face and breasts to their 2 pregnant abdomens,99 which suggests hostility toward the women's fertility. In one study of violent deaths among pregnant women, three out of every four were killed during their first 20 weeks of 1 pregnancy. 100 Research indicates that pregnant women are at higher risk of being abused.101 Once the pattern of violence has escalated, it may not o No Pregnancy Birth Miscarriage Abortion

96 Reardon, supra note 8, at 838. Whether a woman is covertly or overtly coerced into an unwanted 97 Horan, supra note 22, at 1455. abortion, any post-abortion reaction - on either the part of the woman

98 or man - that includes grief, resentment, or anger on the woman's part BURKE & REARDON, supra note 64, at 167-72; R.M. Tolman, Protecting the may increase the frequency and intensity of subsequent hostility and Children of Battered Women, 3 J. INTERPERSONALVIOLENCE476,476-483 (1988).

99 Elaine Hilberman & Kit Munson, Sixty Battered Women, 2 VICTIMOLOGY460, 462 (1977-1978). Physical Violence in Mothers of Newborns, 85 OBSTETRICS & GYNECOLOGY 1031 100 Cara J. Krulewich et aI., Hidden from View: Violent Deaths Among Pregnant (1995); Hortensia Amaro et aI., Violence During Pregnancy and Substance Use, 80 AM. Women in the District of Columbia, 1988-1996, 46 1. MIDWIFERY & WOMEN'S J. PUBLIC HEALTH 575 (1990); 1. McFarlane et aI., Abuse During Pregnancy and HEALTH4,7 (2001). 'Femicide: Urgent Implications for Women's Health, 100 OBSTETRICS& GYNECOLOGY 27, 27-36 (2002). 10l Julie A. Gazmararian et aI., The Relationship Between Pregnancy Intendedness and Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 18 of 26

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domestic conflicts. 102 This hypothesis is supported by clinical suicide, may even gravitat~ toward abusive males who may do the job experience with abused women and at least one survey of women for them. According to one post-abortive woman, participating in post-abortion programs. In the Elliot Institute survey One night during a drunken spree, he held a knife to my chest. of 260 women, fifty-nine percent agreed with the statement that after I told him to kill me, that I wanted to die. I had nothing. No their abortion, "I started losing my temper more easily," and forty- parents, no husband, really, no baby, and no self-respect. eight percent agreed that "I became more violent when angered."lo3 In How could he respect me? I had killed our child. How could this same sample, fifty-six percent reported experiencing suicidal I look at myself in the mirror every day? I was a murderer. I . 106 feelings, with twenty-eight percent actually attempting suicide one or tm Iy wante d to dIe. more times.l04 Approximately thirty-seven percent described This and similar self-reports suggest that post-abortion reactions may themselves as "self-destructive" with another thirteen percent "unsure" 107 (that is, unwilling to rule out that they had become self-destructive).105 aggravate or precipitate domestic violence. Further analysis of this data found that increased post-abortion levels Future investigations of the association between abortion and - of self-hatred, hatred of the male, and hatred of men in general, were c homicide may require examination of police records and interviews all significantly correlated to each other. In addition, suicidal with domestic partners, friends, or relatives. Some cases may be tendencies and self-destructive behavior were statistically associated convoluted. For example, in 1999 a Pennsylvania couple, Michael with shorter tempers and increased levels of anger and violence (p < Oravec and Rhonda Jo Reller, allegedly entered into a suicide pact a .0000 I). In tum, short tempers and self-destructive behavior were also month after an abortion which resulted in profound regret and depression. lOS Oravec survived, subsequently pleaded, and was significantly associated with feeling less in touch with one's emotions, sentenced for the murder of Reller. 109 feeling unable to grieve, faking displays of happiness, and feeling less control over one's life. Women who are angry and self-destructive following an abortion may be less inclined to avoid violent confrontations. Some, who may be unable to commit a direct act of Overall risk of Death from Violence

102Curiously, research has shown that women who have less conflict over a decision As the discussion above suggests, self-destructive tendencies may to abort subsequently have higher levels of hostility. D.T. Moseley et aI., play an important part in any deaths resulting from violence, including Psychological Factors That Predict Reaction to Abortion, 37 J. CUNICAL PSYCHOL. deaths attributed to accidents and homicide. For this reason, a general 276,277-78 (1981). The researchers observed that "[aJ contradiction arises from the assessment of all violent deaths associated with pregnancy outcome fact that if the decision was relatively easy, why the high level of hostility? It may be difficult simultaneously to feel guilt and hostility, and hostility is considered to be a major defensive response to guilt." [d. at 279. If hostility is employed as a defensive reaction to unresolved abortion issues, it may contribute to aggressive behaviors that 106 David C. Reardon, Abortion and Domestic Violence. 4 PosT-ABORTION REv. 13 may make post-abortive women more prone to accidents and homicide in addition to (1996). non-fatal injuries to themselves and others. 107 . Id 103BURKE & REARDON, supra note 64, at 295 questions 7 & 8. The totals reflect the combined responses of those who indicated that they either agreed or strongly agreed 108 Daniel Reynolds, Detective Says Woman Killed Over Abortion, PITTSBURGH TRIBUNE with the statement. REv., May 22, 1999, at C1.

104 [d. at 298 question 19. 109 Man pleads in shooting death, PITTSBURGH TRIBUNE REv., Mar. 13,2001, available at http://library.triblive.com/interconnect/intercon.dll (last visited Apr. 105 Id. at 299 question 3. 17,2004). Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 19 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-I 9 may also be instructive. Researchers in Finland did such an assessment. During the period examined, deaths from violent causes Figure 6 accounted for fifty-five percent of the deaths among women who had been pregnant in the previous year. Women who gave birth had only forty-seven percent of the risk of death from violence (suicide, accident, or violence) as women who had not been pregnant in the Death s from Viol ent Causes prior year (OR = 0.47; 95%.CI = 0.30 to 0.74), while women who had Following First Known abortions had 181 percent of the risk of death as women who had not been pregnant (OR = 1.81,95% CI = 1.31 to 2.50).llO The ninety-five Pregnancy Outcome percent confidence limits (CI) for the latter indicates that after allowing for chance variance in the sample population, it is ninety-five percent likely that the true odds ratio of death from violence lies somewhere • Aborted ~ Delivered between 1.31 and 2.50 times higher relative risk for women who had an abortion in the prior year compared to non-pregnant women. 140 In the California study, there was not a comparison group to non- pregnant women. Instead, after controlling for age and prior 120 psychiatric history, the researchers found that over the full eight year period examined, aborting women had a risk of death from violence that was 178 percent of the risk of death for delivering women (OR = 100 1.78; 95% CI = 1.28 to 2.47).1l1 Figure 6 represents a graph of the rate of death per 100,000 women by pregnancy outcome for this group. It = shows that the disparity in deaths from violent causes is greatest = 80 nearest the event of abortion or delivery and rapidly declines over four =~•.. years, after which differences in risk of death from violent causes are Q,) CI. no longer statistically significant. This time-based effect would seem 111 .c: 60 to support the hypothesis that abortion has a causal direct or indirect l; impact on risk of violent deaths at least within the first four years after Q,) CI an abortion. The decline in risk over four years may be explained by 40 the healing effects of time as women process their grief and overcome self-destructive tendencies that were caused or aggravated by their abortions. 20

0 1-2 3-4 5-6 7-8 110 Mika Gissler & Elina Hemminki, Pregnancy-Related Violent Deaths, 27 SCANDINAVIAN J. PUBLIC HEALTH 54 (1999). Years

III Reardon, supra note 8, at 835. Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 20 of 26 •

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While more research is clearly warranted, these two large record- natural causes may be least likely to become pregnant in the last year of based studies have established that abortion is at least a marker, if not a their lives. causal factor, for increased risk of death from violence. A causal Comparing abortion to birth, however, the risk of death from natural interpretation is supported by other research, clinical experience, and causes was sixty percent higher for women who had abortions compared the self-reports of post-abortive women. The latter is especially to women who gave birth. One possible explanation would be that the important in regard to understanding the causes of death from violence. women who died after an abortion were already in ill health before the Together, the preponderance of evidence clearly refutes the claim that abortions and sought the abortion to protect their health. But the mortality rates associated with abortion are lower than those associated STAKES researchers rejected this hypothesis when an examination of with childbirth. abortion registry records showed that only a single woman in this group While more research is needed, the potential impact of abortion on had her abortion for reasons of maternal health.1'4 deaths from violent causes can be estimated by using the ninety-five Similarly, the comparative mortality study using low-income women percent confidence interval identified in the California study. It is in California showed that over the eight years following a pregnancy ninety-five percent likely that the true difference in relative risk lies outcome, aborting women were forty-four percent more likely to die between 1.28 and 2.47, at least among low-income citizens of from natural causes than women who had delivered (OR = 1.44; 95% CI California. Assuming that this range is similar to all 1.4 million = 1.08 to 1.91).115 women undergoing abortions each year, we can estimate that between The findings would appear to support the view that induced abortion 766 and 4,021 deaths from violent causes each year may be related to produces an unnatural physical and psychological stress on women that or aggravated by a prior abortion.ll2 can result in a negative impact on their general health. This theory is also supported by studies that have examined the amount of health care sought by women before and after induced abortions.' In a review of the records of a group general practice in northwest London treating about 10,000 patients, researchers discovered that on average there was as A Closer Look at Differences in Rates of Death from Natural much as an eighty percent increase in requests for health care services in Causes the year following an abortion compared to the year prior to an abortion. 116 In the Finland study, deaths from natural causes accounted for forty-five percent of the deaths among the recently pregnant women.l13 As seen in Figure 7, the age adjusted odds ratio of dying from natural causes within a year following any pregnancy was lower than that of . 114 E-mailed explanation from Mika Gissler, researcher with the Health Service non-pregnant women. This finding suggests that women who are Research Unit, STAKES, National Research and Development Centre for Welfare and capable of becoming pregnant are simply healthier and less likely to Health, Helsinki, Finland to David C. Reardon (Mar. 8, 2000) (on file with the author).

die of natural causes than women who cannot or do not become 115 pregnant. Conversely, the women who are most likely to die from Reardon, supra note 8, at 838. 116 D. Berkeley et aI., Demands Made on General Practice by Women Before and After an Abortion, 34 J. ROYALCOLLEGEGEN. PRACTITIONERS310, 313 (1984). Another 112 This calculation assumes that the women who did not have abortions would have study examined treatment rates three months before and after abortion and found a the same risk of death from violent causes as those who have deliveries, which was thirty-six percent increased rate of hospital admissions following abortion. The elevated 195.4 deaths per 100,000 women over eight years. hospitalization rates were statistically significant. Tmls Ostbye et aI., Health Services Utilization After Induced Abortions In Ontario: A Comparison Between Community 113 G' I 7 ISS er, supra note , passim. Clinics and Hospitals, 16 AM. J. MED. QUALITY99 (2001). Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 21 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-21

lower health than were losses followed by successful deliveries.118 Figure 7 While the researchers found that miscarriage was also associated with a lower health score, induced abortion was more strongly associated with a lower health assessment and more frequently identified by women as Deaths from Natural Causes the cause of their reduced level of health. More than twenty percent of the women participating in the study expressed a moderate to strong need for professional help to resolve their loss. From these data, the

0.8 psychiatrist who led the research team concluded that pathological grief after the loss of an unborn child, whether by miscarriage or abortion, has a detrimental effect on the psychological and physical health of 0.6 women. He proposed several possible reasons for this: (1) aborting women may be hesitant to discuss feelings of loss or to seek 04 professional help because of the moral, familial, and political controversies surrounding abortion; (2) losses that are not mourned may 0.2 lead to pathological grief which is associated with depression, and depression is associated with a suppression of the immune system,ll9 o increasing the risk of infections and cancers; (3) psychological conflict No Pregnancy Birth Miscarriage Abortion may consume energy that would otherwise be spent in more healthy ways; and (4) prolonged or unresolved mourning may distract the woman from taking care of other health needs or confuse her A number of questionnaire-based studies have also reported an 12o increased rate of health problems post-abortion. Following clinical interpretation of crisis situations. trials of RU-486 on 145 women, 7.6 percent reported increased health In addition to these factors, a history of abortion has been linked to problems two weeks after their medical abortions. This figure rose to heightened anxiety,12I sleeping disorders,122 eating disorders,123 and 13.8 percent by six to eight weeks post-abortion.lI7

Another study examined health ratings compiled by 1,428 patients 118 Phillip G. Ney et a!., The Effects of Pregnancy Loss on Women's Health, 38 Soc. SCI. chosen at random from office visits to sixty-nine general practitioners. & MED. 1193, 1193-94 (1994). The validity of these self-assessments were checked against ratings by their physicians and an independent physician's review of patients' 119 Michael lriwn et a!., Life Events, Depressive Symptoms and Immune Function, 144 AM. J. PSYCHIATRY437 (1987). medical records. The investigators found that women with a history of 120 pregnancy loss, especially abortion, had significantly lower general Ney et a!., supra note 118, at 1193-1200. health ratings than other women. The more pregnancy losses a woman 121 had suffered, the more negative her general health score. Loss of a CATHERINEA. BARNARD, THE LONG TERM PSYCHOLOGICALEFFECTS OF ABORTION 61 (1990); Ellen W. Freeman et a!., Emotional Distress Patterns Among Women Having woman's most recent pregnancy was more strongly associated with First or Repeat Abortions, 55 OBSTETRICS& GYNECOLOGY630 (1980); Jesse R. Cougle et a!., Generalized Anxiety Following Unintended Pregnancies Resolved Through Childbirth and Abortion: A Cohort Study of the 1995 National Survey of Family Growth, 1. ANXIETY DISORDERS (forthcoming 2004). Anxiety following abortion is

II? Warren B. Miller et a!., Testing a Model of the Psychological Consequences of reported by as many as eighty-two percent of women who experience post-abortion Abortion, in THE NEW CIVIL WAR: THE PSYCHOLOGY, CULTURE, AND POLITICS OF maladjustments, with many reporting symptoms of general anxiety related to fear of ABORTION235,244 (Linda 1. Beckman & S. Marie Harvey eds., 1998). punishment from God, fear of another pregnancy, fear of another abortion, fear of others learning of the abortion, fear of making decisions, and preoccupation with thoughts of Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 22 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-22 promiscuity,124all of which can have a direct negative impact on a anxiety among women with a history of abortion128and is a major cause woman's health. Other unhealthy behaviors that have been linked to of respiratory diseases and death. Since lung cancer develops slowly, ab.ortlon are Increase. d aIcohi'0 consumptIOn,125drug abuse,126and however, one would not expect an association between lung cancer and smoking. 127Heavier smoking has been correlated to higher levels of abortion to be detected in a study examining only eight years of death certificates associated with pregnancy outcome, as was done in the California study. A review of the literature on elevated smoking levels death. BURKE& REARDON,supra note 64, at 291-92. following abortion, however, has concluded that even the lowest

122 BARNARD, supra note 122, at 56-58. In the Elliot Institute survey of women who estimate of a two percent increased smoking rate following abortion experienced post-abortion maladjustments, forty-five percent reported bouts of would lead to 4,310 additional cancer cases in the lifetime of the 1.4 insomnia with this reaction statistically associated with nightmares. BURKE & million women having an abortion each year-of whom, at current REARDON,supra note 64, at 125. mortality rates for lung cancer, 3,750 would die from this disease.129 If

123 Mark A. Blais et aI., Pregnancy Outcome and Impact on Symptomatology in a all smoking-related deaths were taken into account, a two percent Cohort of Eating-Disordered Women, 27 INT'L J. EATING DISORDERS 140 (2000); increase in smoking rates among women who have had abortions would. VOUGHT, supra note 94, at 110; BURKE & REARDON, supra note 64, at 187-200, 293. lead to 11,250 additional deaths annually.13O See generally SPECKHARD,supra note 75. Heart disease is another major cause of death that may be impacted 124 by a history of abortion. In the California study, among women with Judith S. Wallerstein et aI., Psychological Sequelae of Therapeutic Abortion in Young Unmarried Women, 27 ARCHIVESGEN. PSYCHIATRY828 (1972). In a survey of only one known pregnancy, during the eight years following their women who had suffered from post-abortion maladjustments, forty-seven percent pregnancies those who had abortions were nearly three times more describe themselves as becoming promiscuous following their abortions. BURKE & likely to die from circulatory diseases (OR = 2.87; 95% CI = 1.68 to REARDON,supra note 64, at 297. 4.89) and over five times more likely to die of cerebrovascular disease

125 See sources cited and accompanying text supra note 91. (OR = 5.46.; 95% CI = 1.60 to 18.65) compared to women who delivered.l3l The impact of abortion on subsequent substance abuse, 126 See sources cited and accompanying text supra note 92. eating disorders, smoking, and substance abuse may explain part of this 127 Drower & Nash, supra note 65, passim; S. Kullander & B. Kallen, A prospective study of smoking and pregnancy, ACTA OBSTETRICA ET GYNECOLOGICAL SCANDINAVICA50, 83-94 (1971); Susan Harlap & A. Michael Davies, Characteristics (1981); Margaret T. Mandelson et aI., Low Birth Weight in Relation to Multiple Induced of Pregnant Women Reporting Previously Induced Abortions, 52 BULL. WORLD Abortions, 82 AM. 1. PUBLICHEALTH 391 (1992). HEALTH ORG. 149 (1975); Ann Aschengrau Levin et aI., Association of Induced Abortion With Subsequent Pregnancy Loss 243 JAMA 2495 (1980); Erik B. Obel, 128 Richard Henshaw et aI., Psychological Responses Following Medical Abortion Pregnancy Complications Following Legally Induced Abortion: An Analysis of the (Using Mifepristone and Gemeprost) and Surgical Vacuum Aspiration: A Population With Special Reference to Prematurity, 26 DANISH MED. BULL. 192 Patient-Centered, Partially Randomised Prospective Study, 73 ACTA OBSTETRICIA ET (1979); A. Lopes et aI., The Impact of Multiple Induced Abortions on the Outcome of GYNECOLOGICASCANDINAVICA812, 817 (1994). Subsequent Pregnancy 31 AUSTRALIAN & NEW ZEALAND 1. OBSTETRICS & 129 Thomas W. Strahan, Women's health and abortion: Risk of premature death in GYNAECOLOGY,41 (1991); Jerker Liljestrand et aI., Characteristics of Young Female Smokers in a Swedish Primary Health Care Area, 11 SCANDINAVIANJ. PRIMARY women from induced abortion, preliminary finding, 5 (2)AsSOCIATION FOR HEALTH CARE 157 (1993); Olav Meirik & Karl-Gosta Nygren, Outcome of First INTERDISCIPLINARYRESEARCHIN VALUES AND SOCIAL CHANGENEWSLETTER 1-8 (1993) Delivery After 2nd Trimester Two-Stage Induced Abortion: A Controlled Historical (subsequently renamed the RESEARCH BULLETIN) [hereinafter Women's health and abortion]. Cohort Study, 63 ACTA OBSTETRICIA ET GYNECOLOGICASCANDINAVICA45 (1984); Carol 1. Hogue, Low Birth Weight Subsequent to Induced Abortion: A Historical 130Id. Prospective Study of 948 women in Skopje, Yugoslavia, 123 AM. J. OBSTETRICS & 131 GYNECOLOGY675 (1975); Carol Madore, A Study on the Effects of Induced Abortion Reardon, supra note 8, at 838. on Subsequent Pregnancy Outcome, 139 AM. J. OBSTETRICS& GYNECOLOGY 139 Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 23 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-23 finding. Also, since it is known that women who abort are at higher associated with abortion and/or delayed childbirth. Women who abort risk of long term clinical depression than women who carry unintended also lose the protective effect of childbirth, which reduces the risk of pregnancies to term,132 and depression is an independent risk factor for cancers of the breast, cervix, colon and rectum, ovaries, endometrium, 137 death from heart disease,133 an association between abortion and heart and liver. Projecting the increased relative risk for contracting just diseases may be mediated by depression. three of these cancers (breast, ovarian, and endometrium) on mortality Depression is also a risk factor for development of several forms of rates associated with each type of cancer, as many as 32,000 cancer 134 135 d . 136 "fi cancer. 8reast cancer an cervlCa 1cancer are a Iso slgm lCant Iy deaths each year may be attributable to negative effects of abortion on maternal health. 138 Record linkage studies examining pregnancy outcomes with death certificates over periods of twenty to forty years 132David C. Reardon & Jesse R.Cougle, Depression and Unintended Pregnancy in the will be required to better identify the actual risk. National Longitudinal Survey of Youth: A Cohort Study, 24 BRIT.MED.J. 151, 151-52 The California study also found that abortion was significantly (2002). As there is a correlation between depression and guilt following abortion, associated with an elevated risk of death from AIDS (OR = evidence that women who had abortions after it was legalized by Roe v. Wade in 1973 2.18; 95% are more likely to express feelings of guilt than women who had abortions before 1973 CI = 1.10 to 4.31 ).139 This finding is consistent with previous research suggests that legalization of abortion may be associated with higher risk of post- identifying higher rates of HIV-l infection among women who have abortion depression. See Douglas Brown et aI., Prolonged Grieving After Abortion: A abortions compared to those who deliver. 140 Abortion may be a Descriptive Study, 4 J. CLINICALETHICS118 (1993). Legalization of abortion may contributing factor in AIDS since pelvic inflammatory disease, which is have increased the risks that undergo "unwanted" abortions in response to the pressure of other persons. When abortion was not readily available, the hurdles women had to a relatively common complication of abortion, 141may increase the risk go through to find a legal or illegal abortion may have served as a mechanism for screening out women who were ambivalent and for reducing the pressure from others previously noted, smoking and promiscuity, which are risk factors for cervical cancer, to have an abortion. Since 1973, high levels of ambivalence are common among are known to increase following abortion. Abortion may also have a direct impact via women seeking an abortion. See MARY K. ZIMMERMAN,PASSAGETHROUGH mechanical trauma and infection associated with the surgery, chronic inflammatory ABORTION:THE PERSONALANDSOCIALREALITYOF WOMEN'SEXPERIENCES(1977); lesions, and general endocrine stress. See Larissa I. Remennick, Induced Abortion as M.B. Bracken, A Causal Model of Psychosomatic Reactions to Vacuum Aspiration Cancer Risk Factor: A Review of Epidemiological Evidence, 44 J. EPIDEMIOLOGY& Abortion, 13 SOCIALPSYCHIATRY135 (1978); DAVIDC. REARDON,ABORTEDWOMEN, COMMUNITYHEALTH259 (1990). See also A. Hildesheim et aI., HPV Co-Factors SILENTNo MORE16-17 (1987). Related to the Development of Cervical Cancer: Results from a Population-Based 133Brenda W. J. H. Pennix et aI., Depression and Cardiac Mortality, 58 ARCHIVES Study in Costa Rica, 84 BRIT. J. CANCER1219 (2001); Ramiro Molina et aI., Oral Contraceptives and Cervical Carcinoma in Situ in Chile, 48 CANCERRESEARCH1011 GEN. PSYCHIATRY221 (2001); Robert M. Carney et aI., Depression and Coronary (1988); F. Parazzini et aI., Reproductive Factors and the Risk of Invasive and Heart Disease: A Review for Cardiologists, 20 CLINICALCARDIOLOGY196 (1997); K. Intraepithelial Cervical Neoplasia, 59 BRIT. J. CANCER 805 (1989); THOMASW. Ranga Rama Krishnan, Depression as a Contributing Factor in Cerebrovascular STRAHAN,DETRIMENTALEFFECTSOFABORTION:AN ANNOTATEDBIBLIOGRAPHYWITH Disease, 140 AM. HEART1. 70 (2000); O'Connor et aI., Depression and Ischemic Heart COMMENTARY214-19 (3d ed. 2001). Disease, 140 AM. HEARTJ. 63 (2000). 137 STRAHAN,supra note 136, 206-27. 134Robert W. Linkins & George W. Comstock, Depressed Mood and Development of Cancer, 132 AM. J. EPIDEMIOLOGY962, 962 (1990). 138Women's Health and Abortion, supra note 129.

135Joel Brind et aI., Induced Abortion as an Independent Risk Factor for Breast 139 Reardon, supra note 8, at 838. Cancer: A Comprehensive Review and Meta-Analysis, 50 J. EPIDEMIOLOGY& COMMUNITYHEALTH481 (1996). Twenty-eight studies examining data relevant to 140Damiano D. Abeni et aI., Deliveries, Abortion and HIV-I Infection in Rome, 1989- breast cancer and prior reproductive history are examined in this meta-analysis. 1994, 13 EUR. J. EPIDEMIOLOGY373, 373-374 (1997). A Desgrees et al. HIV-1 Infection and Reproductive History: A Retrospective Study among Pregnant Women: 136Numerous studies show that there is a twofold to threefold increased risk of cervical Adidjan, Cote d'lviire, 9INT'L J. STD & AIDS 452 (1998). cancer associated with prior history of abortion. The increased risk of cervical cancer associated with prior abortion history may be mediated through numerous factors. As 141 Lars Heisterberg, Pelvic Inflammatory Disease Following Induced First-Trimester Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 24 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-24 142 of HIV transmission. Increased levels of substance abuse and study, after controlling for prior mental illness, researchers found that promiscuity following abortion may also contribute to a higher risk of women who had abortions were three times more likely to die from 143 HIV infection and death from AIDS. causes attributed to mental disease than women who carried to term.148 It is also known that induced abortion is associated with a subsequent risk of placenta previa and premature delivery.144Increased rates of genital tract infection, pelvic inflammatory disease, Conclusions endometritis, ectopic pregnancy, retained placenta, preeclampsia, and other complications of pregnancy and delivery in subsequent In arriving at the conclusion that abortion's mortality rates are lower pregnancies have also been identified in the literature.145 All of these than those of childbirth in Roe v. Wade, Justice Blackmun relied on the complications are associated with higher risk of maternal and neonatal studies and opinions of population control advocates Christopher Tietze, death. 146Even if these deaths are actually traceable to latent abortion Malcolm Potts, and Lawrence Lader, all of whom were zealous morbidity (scarring of the uterus, for example), these deaths would be promoters of liberalized abortion laws.149 The studies they relied on, classified as maternal deaths rather than abortion-related deaths, and however, had many methodological problems, including very limited would therefore confound the comparison of mortality rates between access to patients for follow-up, no control group of delivering women, abortion and delivery. and lack of an objective standard for comparing mortality rates of Abortion is also associated with a subsequent increased need for delivering and aborting women. The focus of these abortion advocates treatments for mental illness compared to delivery.147In the California appeared to be limited to identifying the risk of death from short-term complications of abortion such as septic infection or therapeutic misadventure. But subsequent experience has shown that abortion can Abortion, 35 DANISHMED. BULL. 64 (1988); Jette Led Sorensen et aI., Early- and have both subtle and profound effects on women's psychological and Late-Onset Pelvic Inflammatory Disease Among Women with Cervical Chlamydia physical wellbeing. In the 1960s and early 1970s, abortion advocates Trachomatis Infection at the Time of Induced Abortion--A Follow-Up Study, 22 erroneously believed, without any recourse to supporting data, that the INFECTION242 (1994); Susan D. Hillis et aI., Delayed Care of Pelvic Inflammatory risk of death from suicide after an abortion was negligible while the risk Disease as a Risk Factor for Impaired Fertility, 168 AM. J. OBSTETRICS& GYNECOLOGY1503 (1993). of suicide among women with unintended pregnancies was high. Similarly, in making their estimates of abortion mortality rates, abortion 142 Jay A. Levy, Transmission of AIDS: The Case of the Infected Cell, 259 JAMA advocates did not consider the impact of abortion morbidity on 3037,3037 (1988). longevity. Death arising from conditions created or aggravated by

143 Judith A. Stein et aI., Psychosocial Correlates and Predictors of AIDS Risk abortion complications, such as ectopic pregnancy, pelvic inflammatory Behaviors, Abortion, and Drug Use Among a Community Sample of Young Adult disease, depression, and breast cancer, should also be considered in any Women, 13 HEALTHPSYCHOL.308, 308-15 (1994).

144 John M. Thorp et aI., Long-Term Physical and Psychological Health Consequences Abortion and Childbirth,168 CANADIANMED. ASS'N J. 1253, 1255-56 (2003); Priscilla of Induced Abortion: Review of the Evidence, 58 OBSTETRICAL& GYNECOLOGICAL K Coleman et aI., State-funded abortions vs. deliveries: A .comparison of outpatient SURV.67 (2003). mental health claims over five years, 72 COLEMANAM. J. ORTHOPSYCHIATRY141-52 (2002); Henry P. David et aI., Post-Abortion and Postpartum Psychotic Reactions, 13 145 See Strahan, supra note 136, at 168-204; Thomas W. Strahan, Detrimental Effects FAM.PLAN.PERSP.88,89 (1981). of Abortion: Supplement No. I (Supp. 2002).

148 Reardon, supra note 8, at 838. The odds ratio for death from mental disease was 146 Thomas W. Strahan, Induced Abortion as a Contributing Factor in Maternal 3.21,95% CI 1.11 to 9.27.1d. Mortality or Pregnancy-Related Death in Women, 10 RESEARCHBULLETINI (1996).

149Roev. Wade, 410 U.S. 113, 149n.44(1972). 147 David C. Reardon et aI., Psychiatric Admissions of Low-Income Women Following •. Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 25 of 26

Deaths Associated with Abortion Compared to Childbirth--A Review page-25

comparison of mortality rates. Nor did their appraisals recognize nor deliveries which have a maternal mortality rate of approximately 100 account for the protective effects of early and frequent childbirth per 100,000 c-section deliveries, compared to only 1.1 per 100,000 for against a variety of cancers and other ailments . vaginal deliveries.ls2 The hundred-fold higher mortality rate reported . The original comparisons of reported abortion deaths to national following c-section. deliveries compared to vaginal deliveries may maternal mortality rates relied upon in Roe were also flawed by the reflect a combination of the following three factors: (1) women who are fact that even the deaths attributable to immediate complications of ill or faced with higher-risk deliveries are more likely to be delivered by abortion occurred primarily among healthy women who had little or no a c-section; (2) a coroner is less likely to miss the fact that a woman risk of death from childbirth. In this sense, they were "extra" deaths. who has undergone a recent c-section was recently pregnant; and (3) They were not simply unsuccessful attempts to save these women from there are significant surgical risks associated with c-sections and this dying during dangerous pregnancies and deliveries. In fact, there are procedure is arguably overused.ls3 Since a doctor should normally no studies that have established when, if ever, abortion reduces a anticipate that a healthy, young pregnant woman is able have an woman's risk of death compared to childbirth. ISO In one of the few uncomplicated vaginal delivery, a strong argument can be made that the studies undertaken to determine if maternal deaths could have been most relevant comparison for healthy women would be a comparison of avoided by abortion, it was concluded that therapeutic abortion would mortality rates associated with abortion compared to those associated not have prevented any of the twenty-one maternal deaths which with a vaginal delivery. Conversely, for women with known health occurred among the 74,317 pregnancies examined.lsl problems, there is not yet any research showing that abortion is less It is also noteworthy that as many as ninety percent of maternal dangerous for these women than childbirth;ls4 there is only the deaths related to childbirth are associated with caesarean section presumption that this may be true. Clearly, carefully designed case- control studies are needed to determine when, if ever, abortion is associated with a reduced mortality risk compared to delivery. 150 John F. Murphy & Kieran O'Driscoll, Therapeutic Abortion: The Medical Argument, 75 IRISHMED.J. 304, 305-06 (1982). While it is known that some illnesses Medical intervention in a health natural process such as pregnancy increase the risk of death during pregnancy or delivery, there does not appear to be any should only be undertaken when there is clear medical evidence that the studies that have demonstrated lower mortality rates among women with a particular treatment produces clearly defined benefits that outweigh any related class of disease who elect abortion. At least some researchers have concluded that risks. As David Grimes, M.D., has noted, interventions based on while it may be inadvisable for women with these diseases to become pregnant, once they are pregnant there is no evidence to support the view that abortion poses less risk to their health than careful management of their pregnancy. Id.

152 M. Lanskaet aI., Mortality From Abortion and Childbirth, (letter), 250 JAMA 361- lSI Id. According to the authors, 362 (1983). Among the 21 maternal deaths, 7 were not connected with pregnancy and for this reason would not have been prevented by therapeutic abortion, 11 were a direct result 153 S. Taffel et aI., Trends in the United States Cesarean Section Rate and Reasons for of pregnancy but, as these cases suffered from complications which could not have the 1980-1985 Rise, 77 AM. J. PUBLIC HEALTH955 (1987). been forseen, the question of therapeutic abortion would not have arisen, and 3 were the result of chronic disease which deteriorated to such a degree as to lead to a fatal IS4 Murphy & O'Driscoll, supra note 150, at 305 (noting that even in cases such as outcome. Eisenmenger's Syndrome, which poses a serious risk to a pregnant woman's life, the same disease that makes delivery problematic makes any surgery, including abortion, Id. at 305. In a careful analysis of each of the three cases where chronic disease was problematic to the point where the surgery may pose risks that equal or exceed those present, the researchers concluded that a therapeutic abortion would not have been associated with a spontaneous delivery. This observation highlights an important recommended in any of these cases. They also noted that there is a severe absence of problem: Even after decades of experience with abortion, there have not been any case- research indicating when, if ever, abortion might actually reduce the risk of death for control studies published showing that abortion has statistically significant benefits pregnant women with severe health problems, particularly since the abortion itself may compared to childbirth. This is true in regard to both the general population of healthy involve as much or more risk than childbirth. women and in regard to the population of unhealthy pregnant women. Case: 3:13-cv-00465-wmc Document #: 245-2 Filed: 06/11/14 Page 26 of 26 "'" .". .

Deaths Associated with Abortion Compared to Childbirth--A Review page-26

theories that are not substantiated by research place patients at risk of pregnancy, poses a significant risk to women's health. Since Roe injury: "Uncritical thinking has hurt women and children around the established comparative mortality rates as the standard for determining world. Notable examples include diethylstilbestrol, the Dalkon Shield, when states can regulate abortion to protect the health interests of and bottle feeding. We cannot afford, either economically or ethically, women, this new medical evidence would appear to be sufficient to to allow good intentions to dictate practice without the check of establish a compelling state interest in regulating abortion throughout all scientific controls. Our practices need dispassionate scientific stages of pregnancy. scrutiny.,,155 -, While some medical experts will certainly continue to defend the *David C. Reardon, Ph.D., is a biomedical ethicist, the director oftheElliot opinion that abortion is a safe alternative to childbirth, this opinion can Institute, and a widely published researcher on the psychological and physical no longer be characterized as a "now-established fact.,,156It is at best effects of abortion on women. an unsubstantiated opinion, most likely a hope, and at worst, an tThomas W. Strahan, J.D., died on November 13,2003. He was a civil rights ideological mantra. While "[d]octors often differ in their estimate of lawyer who practiced law in Minneapolis, Minnesota and editor if Detrimental comparative health risks and appropriate treatment,,,157responsible Effects of Abortion: An Annotated Bibliography with Commentary. differences of opinion must be reconcilable with empirical evidence. In the case at hand, it is clear that prior comparisons of mortality rates ~John M. Thorp, Jr., M.D., is the McAllister Distinguished Professor of associated with abortion and childbirth have been crudely constructed Obstetrics and Gynecology at the University of North Carolina School of on the basis of an incomplete and inaccurate reporting system. Using Medicine. the standards developed for evidence-based medicine, the recent record-based case-control studies represent the best available medical **Martha W. Shuping, M.D., graduatedjrom Wake Forest University Medical evidence on this issue and supercede any "expert opinions" that School, Winston-Salem, North Carolina, in 1984, and completed her psychiatry diverge from this evidence.158 residency at North Carolina Baptist Hospital in 1988. She has been in private practice in Winston-Salem since 1991. After thirty years of experience with legal abortion in the United States, it is now clear that mortality risks associated with abortion significantly exceed those associated with childbirth, both in the short term (under one year) and in the longer term. While statistical Related Studies Subsequently Published association is not proof of causation, it is clear that abortion is, at the very least, a marker for elevated mortality rates. In the context of the Gissler M, Berg C, Bouvier-Colle MH, Buekens P. Methods for additional studies reviewed in this paper, it is also clear that the identifYing pregnancy-associated deaths: population-based data from interpretation of a causal effect cannot be ruled out. It is therefore Finland 1987-2000, 18 PAEDIATR PERINAT EPIDEMIOL, 448,55 reasonable for legislators to conclude that abortion, at any stage of (2004). Reports that 73% of pregnancy associated deaths and 94% of abortion associated deaths are missed when record-linkage is not used.

155David A.Grimes et aI., Teaching Critical Appraisal to Medical Students in Gissler M, Berg C, Bouvier-Colle MH, Buekens P. Pregnancy- Obstetrics and Gynecology, 92 OBSTETRICS& GYNECOLOGY877, 880 (1998). associated mortality after birth, spontaneous abortion or induced , 1987-2000, 190 AM JOB GYN, 422-427 (2004). 156 Roe, 410 U.S. at 163.

157 Stenberg v. Carhart, 530 U.S. 914, 937 (2000). Gissler M, Berg C, Bouvier-Colle MH, Buekens P. Injury deaths, suicides and homicides associated with pregnancy, Finland 1987-2000, 158 See generally Grimes et aI., supra note 155. EURJ PUBLIC HEALTH (2005); Case: 3:13-cv-00465-wmc Document #: 245-3 Filed: 06/11/14 Page 1 of 2

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Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 16. No.2, pp. 247-261. 2002_ . t,l doi: IO.I053jbeog.2002.0274. available online at http://www.idealibrary.com on 10 E,~l, BEST PRACTICE 9 ,\t RESEARCH

Surgical abortion

Gillian M. M. Flett FRCOG, MFFP Square 13, Centre for Reproductive Health, 13 Golden Square, Aberdeen, ABIO IRH, UK

Allan Templeton MD Hons, FRCOG Professor Department of Obstetrics & Gynaecology, University of Aberdeen, Aberdeen Maternity Hospital, Cornhill Road, Foresterhill, Aberdeen AB9 2ZD, UK

This review of surgically-induced abortion focuses on conventional first trimester suction evacuation. Manual vacuum aspiration at early gestations and dilatation and evacuation at more advanced gestation are also considered. The place of surgical abortion in contemporary abortion practice is reviewed alongside developments in medical abortion. There is still debate about the best method for later abortions. Patient choice and pre-procedure assessment are considered fundamental to practice. The importance of antibiotic prophylaxis or infection screening is highlighted. The value of ultrasound emerges. The need for cervical priming is considered along with choice of suitable pharmacological agents. Current practice and the procedure of surgical abortion is outlined. Complications and strategies to minimize risk are detailed. The overview concludes with consideration of the impact on future reproductive health.

Key words: surgically induced abortion; cervical priming; mifepristone; misoprostol; ultra- sound; antibiotic prophylaxis; complications.

Surgical abortion is one of the most commonly practised gynaecological surgical procedures. The late 1980s and 19905, however, saw exciting, new developments of medical methods for early abortion and improvement of medical methods for mid- trimester termination. These developments have extended patient choice and diversified the provision of abortion services. This review focuses on conventional surgical abortion but also briefly considers manual vacuum aspiration and late dilatation and evacuation for early and later gestations, respectively. All aspects of surgical abortion care are considered against a background of currently available evidence. It is this evidence base which underpins our clinical training programmes and everyday clinical practice for the provision of high-quality abortion services.

CHOOSING SURGICAL TERMINATION

Legal criteria for abortion are individual to the country of practice. In general, in addition to fulfilling legal statute, a clinician will wish to be certain that a woman has e-mail: [email protected] Telephone: (01224) 555117 Fax: (01224) 555123 1521-6934/02/$ - see front matter Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 2 of 15

248 G. M. Flett and A. Templeton

considered her options carefully, is sure of her decision for abortion and gives informed consent. Gestation is a major determinant of options available for terminating a pregnancy, and pregnancy counsellor, clinician and client will each play a role in determining the most suitable method which is acceptable to the woman, as well as being safe and effective. Additionally reference should be made to guidelines for good practice such as the RCOG Guidelines in the UK.1 Clinical practice in three large Scottish units indicates that more than half of eligible women opt for medical methods when given a choice at early gestations up to 9 weeks, and Scottish abortion statistics reveal that 40% of all terminations in Scotland are performed medically.2 Patient surveys have confirmed that women value being offered a choice of method appropriate to the gestation of their pregnancy.3-S A recently completed randomized controlled trial of medical and surgical termination at over 9 weeks to 13 weeks gestation undertaken in Aberdeen confirms previous pilot work that medical abortion is also safe and effective at these gestations and will further extend patient choice at gestations where previously surgical abortion was the only option.6 The RCOG guideline development group recommended that conventional suction termination should be avoided at gestations under 7 weeks on the basis that suction termination at these very early gestations is three-times more likely to fail to remove the gestation sac than those performed between 7 and 12 weeks.? The guideline for UK practice advocates medical abortion under 7 weeks or waiting until 7 weeks or over for conventional surgical termination. I Manual vacuum aspiration (MVA) was largely abandoned in the 19705following legalisation of abortion, because of high failure rates, but the technique has been redeveloped under strict protocols, such as Edward's protocolS, and a complete abortion rate of> 99% is reported in their series. There are no randomized trials comparing MVAtechniques with the mifepristone prostaglandin regimens in current use. Published trials involved single-agent prostaglandin medical regimens, which had unacceptable failure rates and which have been superceded.9 Selection of medical or surgical method for later abortion, particularly beyond 15 weeks, is usually dependent on the availability of healthcare personnel who are trained and willing to participate in either late dilatation and evacuation. The medical regimen most widely used is based on mifepristone followed by prostaglandin doses. Regrettably, there has been no formal comparison in clinical trials between second trimester dilatation and evacuation and modern methods of medically managed mid-trimester medical termination. It is certainly true that as gestational age increases, the safety of second trimester surgical abortion depends highly on the operator's skill and experience. The current situation is that clinics and clinicians usually set their limits for operative care based on these considerations. It should be noted that hysterotomy with its associated higher morbidity and mortality has virtually disappeared. Choice is now an integral part of abortion care and information, coupled with sensitive counselling, is essential to help the woman in selecting an abortion method that is right for her and to optimise the abortion experience. The factors that determine women's choices for medical or surgical abortion are complex, and a detailed consideration is not in the scope of this chapter. In brief, the chief advantages of the surgical method are that it is simple and quick and associated with a low risk of complication or failure. Some women can feel a lack of control over a surgical procedure, whereas others prefer that they remain unaware and that the procedure is undertaken by their clinician. Of course, where medical termination fails, a surgical approach has to be adopted, a situation which cancels some of the benefits of the medical procedure (Table I). Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 3 of 15

Surgical abortion 249

Table I. Methods of surgical abortion at different gestations.

Weeks gestation from LMP 4 24

< --- >------> < ------> Manual vacuum aspiration Dilatation and evacuation by specialist practitioners

< ------> ..__._----> Suction termination under general or local anaesthetic

PATIENT ASSESSMENT AND PREPARATION

Whereas counselling and .procedure choice can dominate the consultation, pertinent medical history must be obtained and documented. It is only occasionally that the medical history is complicated and these are usually serious pre-existing conditions where the abortion care is best planned in consultation with relevant specialists. Agreement for cross consultation should be confirmed with the woman but, despite the sensitivities of abortion, it would be unusual for a woman to withhold her permission. For serious medical conditions the risks of abortion are always lower than the risks of continued pregnancy. This health screening gives an opportunity to organize any additional non-gynaecological investigations which are required and otherwise confirm suitability for an ambulatory care surgical procedure. Some centres find patient self-completion questionnaires useful, with the clinician picking up any positive responses for more detailed attention. E"nquiry about previous use of contraception and discussion about intended use of contraception can usually be integrated with this consultation. Body mass index and blood pressure are checked and physical examination is limited to auscultation of chest and heart. An idea of gestational age will have been gained from the menstrual history but, given the inaccuracies of menstrual recall and limitations of bimanual pelvic examination, gestation is more accurately determined by ultrasound scan (either abdominal or vaginal) as relevant to anticipated gestation. Viability and pregnancy location is also confirmed. The scan should be undertaken in a sensitive setting and manner. The imaging screen is usually turned away from the patient, although occasionally some women make a specific request to see the ultrasound examination in progress, or even to have a photograph of the scan. Although there are observational studies, there are no randomized trials on the value ofthe pre-abortion ultrasound. All patients have blood sent for determination of ABO and Rhesus status with antibody screening. All unsensitized Rhesus negative women should be given anti-D immuno- globulin. A full blood count can be useful to screen for anaemia and also as a baseline for comparison in the event of any substantial blood loss associated with the procedure. This is also a useful opportunity to confirm immunity to rubella, and offer immunisation subsequently if not immune. Some centres offer testing for human immunodeficiency virus and hepatitis Band C at this time, but unless a policy for routine screening has been adopted and accepted, additional counselling would be required, and in the meantime such testing remains on a selective basis. Although not essential to abortion care, it is an opportunity to Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 4 of 15

250 G. M. Flett and A. Templeton

check that cervical screening is up to date and, where it is not, opportunistic cervical screening can be offered, ensuring that the result can be communicated to the woman and appropriate action taken on any abnormal results. Pre-procedure screening for genital tract infection helps to identify pathogens which increase the risk for post-abortion infection and pelvic inflammatory disease as well as long term sequelae of tubal infertility and ectopic pregnancy. The most important of these are C. trachomatis and N. gonorrhoea.lo-l2 A full screen, including for sexually transmitted infections (STI), allows for follow-up and partner notification and treatment to avoid re-infection. Some advocate antibiotic prophylaxis at the time of abortion and Sawaya et al published a meta-analysis of randomized trials with a reduction in risk for subsequent infective morbidity of around 50%.13 Prophylactic antibiotics alone do not allow for contact tracing and therefore leave women at risk from re-infection. Blackwell et al14 advocate the 'belt and braces' poiicy of a prophylactic regimen against chlamydia and bacterial vaginosis along with a full STI screen. Penney et all~ compared prophylaxis and a 'screen and treat' policy in a randomized trial and concluded that universal prophylaxis is at least as effective as this in minimizing short-term infective morbidity and can be provided at less cost. The Guideline Development Group for the RCOG in the UKI concluded that all abortion services should adopt a strategy to reduce post-abortion infective problems. The minimum recommendation was antibiotic prophylaxis against chlamydia and bacterial vaginosis. Metronidazole I g rectally at the time of abortion with I g oral azithromycin post-procedure would be one suitable regimen. Azithromycin seems to be increasingly favoured to a 7-day course of doxycycline where compliance can be a problem.

CERVICAL PRIMING

There is evidence that cervical priming ahead of surgical abortion reduces the complications of cervical injury, uterine perforation, haemorrhage and incomplete I evacuation. 6-18 Risk factors for cevical damage include younger patient age and increasing gestation, especially in multiparous women, is associated with uterine perforation.19 In North America there has been wider use and experience with osmotic dilators, particularly for later first trimester abortion and the evidence base largely relates to these, whereas the pharmacological agents are mostly used in the UK. Mifepristone and the prostaglandin EI analogues, gemeprost and misoprostol are effective cervical priming agents (Table 2). In the UK gemeprost is the licensed preparation although there is evidence from randomized controlled trials ~RCTs) that misoprostol is an effective alternative and costs less, but is unlicensed.2o• I Likewise there is evidence from RCTs that the anti-progesterone mifepristone is also an effective priming agent.22•23 Mifepristone has a higher cost than misoprostol but not gemeprost. It has the disadvantage of requiring administration 36-48 hours ahead of

Table 2. Cervical priming agents in UK practice.

• Gemeprost I mg vaginally, 3 hours ahead of surgery (refer to data sheet) • Misoprostol 400 I!g (2 x 200 I!g tabs) vaginally, 3 hours ahead of surgery* • Mifepristone (refer to data sheet)

*No product licence for this use Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 5 of 15

Surgical abortion 251 the abortion but has the advantage that it can be administered orally. Published evidence has shown mifepristone to be as effective as 400 f..lgoral misoprostol 24, but more recent evidence suggests that mifepristone has higher efficacy than gemeprost and misoprostol when given 48 hours ahead of surge~ and thus the effect could be related to the duration of exposure to the drug.2S- 7 Pre-operative bleeding is a potential problem and women need to be warned about the risk of vaginal bleeding and possibly abortion occuring pre-operatively. Although currently appearing the most effective cervical priming agent, cost and availability in comparison to misoprostol will probably result in selective use, perhaps for young nulliparous women who frequently present with more difficult cervical dilatation. The efficacy of vaginal misoprostol for priming relates to the dose administered and the time interval to surgical evacuation. Optimal time interval for administration is at least 3 hours before surgery.28 Even under study conditions, we have found this difficult to achieve where women are admitted as outpatients for a dedicated theatre list. Misoprostol however is cheap, does not require special storage conditions and can be administered orally or vaginally, although the oral route is associated with an unpredictability of action unless administered in the few hours immediately before surgery.21

CURRENT PRACTICE

Surgical abortion is performed in either a hospital or dedicated facility in a designated clinic. North American data would suggest that procedures performed in an office setting are as safe as those performed in hospitals, with lower costs.29,30 Vacuum aspiration is the standard procedure using a plastic cannula for aspiration with complete avoidance of using sharp instruments within the uterus, thereby minimizing the risk of uterine perforation. General anaesthesia is standard practice in the UK although use of local anaesthesia paracervical block, with or without sedation, is increasing and certainly should be offered. Suction termination may be safer under local anaesthesia. Studies comparing the safety of local and general anaesthesia have been observational or only partially randomized.31-33 Many clinicians do not perform surgical abortion under 7 weeks gestation because of the risk of failure to remove the pregnancy. However, with the current use of highly sensitive pregnancy tests, many women now present at early gestations shortly after their missed periods. For those women it is not appropriate to defer the abortion to a suitable gestation for surgery, and their preference might not be for medical abortion or indeed, in certain circumstances, there may be contra-indications to medical abortion. The 19905saw renewed interest in MVA, a procedure which had its origins back in the 1960s in relation to the practice of ''. MVA can take a few minutes longer than the electronic vacuum procedures, especially as gestation approaches 9 weeks. Uterine evacuation is accomplished using a 4, 5 or 6 mm flexible plastic cannula attached to a 50 cc manual vacuum syringe. MVA was largely abandoned after the legalisation of abortion because of its failure rate but modern protocols rely on human chorionic gonadotroph in (hCG) assays, high resolution ultrasound pre- and post-procedure and careful immediate tissue inspection. Although a technique largely re-established in the US, there is substantial current interest in establishing it within UK practice. The technology, of course, is particularly suited for the developing world because it does not depend on the availability of electricity or anaesthetics. It is also possible that with proper supervision and training, healthcare workers other than medical practitioners could Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 6 of 15

252 G. M. Flett and A. Templeton

potentially be trained to perform these procedures safely. MVA might also be useful following failed medical abortion where full theatre facilities are not readily available.

THEATRE/PROCEDURE ROOM SET UP

Whether the abortion is being performed in a day surgery unit, theatre suite within a hospital or in a free standing clinic facility with a procedure room, the basic requirements are the same. The choice of anaesthesia depends on available resources, preferences of clients and clinicians and the risk assessment of the provider environment. The overall aim is to provide a safe, comfortable and relaxing environment. The ideal is to be able to provide all methods of anaesthesia from a simple paracervical block, with or without additional sedation, through to general anaesthesia. It is best if the operating table is hydraulically operated and even if not it should provide comfortable support in the lithotomy position for awake patients. The table must be able to adapt to head-down tilt which could be necessary in anaesthetic emergencies or following a vasovagal episode or major blood loss. The area should be adequately staffed and there are likely to be guidelines in place for minimum recommended staff numbers. The presence of the anaesthetist is important. The operator should have a comfortable seat with good lighting on the 'operating area. There should be an electrically powered vacuum pump connected by plastic tubing, disposed of between each case, along with a disposable receptacle for products. Manual vacuum aspirators may also, or alternatively, be available. Theatre greens and face masks and eye protection should be used to avoid exposure of the operator to the hazard of contamination with body fluids. Disposable equipment should be used. wherever possible and there should be adequate arrangements for sterilization of reusable instruments. There should be a policy in place for the safe and sensitive disposable of products by incineration. In the UK this follows guidance from the NHS executive. The layout of surgical trays should be consistent and simple so that instruments can be quickly and easily located. Typical trays would have a speculum, vulsellum or tenaculum, sponge forceps, polyp forceps, large and small uterine curette and a series of graduated cervical dilators. There should be a small basin for holding antiseptic solution and sponges or equivalent for cleaning down. Disposable plastic suction cannulae, such as the Karman suction curette should be available in a range of sizes, with the appropriate size being provided on the operator's request.

PERFORMING SURGICAL ABORTION

As with all surgical procedures, good technique is fundamental. Aseptic technique should be observed with careful and gentle instrumentation to avoid injury to cervix or uterus. The operation itself is simple with low complication rates, but skill and experience are important so that serious complications are quickly recognized and remedied. Talking awake patients through the procedure, warning them of the various sensations which they may experience is helpful to keeping them comfortable and reassured, and reduces the chances of any unexpected sudden movements. The patient should be well positioned on the theatre table with her bottom just beyond the edge of the table as she lies in lithotomy position. This helps to incline the pelvis posteriorly and also prevents any limitation in the manipulation of instruments. Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 7 of 15

Surgical abortion 253

After routine asepsis and draping, a gentle bimanual examination should be undertaken to confirm the position, size and shape of the uterus. Any extreme ante- flexion or retro-flexion should be noted. The speculum is then placed into the vagina to visualize the cervix and for the awake patient it would be usual to cleanse the cervix at this stage. Again for an awake patient, local anaesthetic is injected into the lip of the cervix where the vulsellum or tenaculum is to be applied and a four quadrant paracervical block administered with local anaesthetic. Where the uterus is retro- verted it is sometimes useful to place the tenaculum on the posterior lip ofthe cervix to allow more effective traction. In these situations, if the tenaculum is placed on the anterior lip traction can simply result in closing off the cervical canal further to the passage of instruments. Traction on the tenaculum straightens the angle between the cervical canal and the uterine cavity and dilators can be passed to a depth just beyond the internal cervical os. The operator should completely avoid touching the portion of any instruments entering the uterus to maintain an aseptic technique. Assorted dilators are available. In our own unit we use Hegar dilators, but in the US Pratt dilators are favoured. Blunt dilators, such as Hegar, increase in size more rapidly than tapered dilators and require fewer instrument passes, although it is said more tapered dilators are less traumatic. It is best to hold the dilators to prevent uncontrolled forward movement as the dilator has force applied to it, to overcome the resistance at the internal os. With experience the operator becomes familiar with the typical sensation of correct passage of the dilator along the cervical canal. Graduated dilators are passed in sequence to achieve the diameter required to accommodate the cannula chosen for the gestation. We use straight rigid plastic Karmen suction curettes and find sizes 6, 8 and 10 mm adequate for gestations from 6 to 13 weeks gestation. Surgeons vary in regard to their preference for width of dilatation and there are no controlled trials for outcome from lesser or greater dilatation in first trimester surgical abortion. Smaller cannulae for later gestations tend to be associated with a slower procedure and more bleeding. Where the cervix is tight or the course of the cervical canal uncertain, we find a flexible, ultra-thin Pipelle endometrial biopsy cannula useful to navigate the cervix before formal dilatation. In difficult cases ultrasound can help to provide a view of the cervix and dilator for dilatation under ultrasound vision. Applying antiseptic to the dilator tip can also reduce resistance and leaving the previous dilator in the canal for a brief time helps subsequent dilatation. The uterus might need to be evacuated with a smaller cannula than would normally be used at the gestation, although if the cervix cannot be safely dilated medical abortion is an alternative. The suction cannula should be positioned in the mid to upper fundus and when the operator is sure of correct placement, the suction can then be turned on. The cannula should be gently rotated and a back-and-forth motion used, withdrawing only as far as the internal os until the flow of tissue and fluid ceases, and a gritty sensation is felt as the cannula moves against the wall of the contracted empty uterus. The cannula can then be withdrawn from the cervix. Sometimes larger volume products can obstruct flow and some gentle pressure may be required to clear the suction tubing or the vacuum might need to be broken altogether, by removal of the cannula, to allow the system to clear. Sometimes sponge forceps are required to remove products in the canal. For later gestation evacuations it is often useful to reduce the cannula size to complete the procedure more easily as the uterus begins to contract down. There is inevitably some degree of variation in technique amongst operators. Because of low rates of haemorrhage, oxytocics are not routinely administered. Both RCTs that Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 8 of 15

254 G. M. Flett and A. Templeton

evaluated the role of oxytocics during surgical abortion showed significant reduction in blood loss but were not of sufficient power to examine reduction in potentially life- threatening haemorrhage. Syntometrine is reported to be more effective than oxytocin or ergometrine alone.34,35 Placental tissue, and at later gestations fetal parts, will be seen coming away, although formal inspection of products is less practised in UK units, as health and safety protocols are directing a trend to the use of sealed units to minimize exposure to biohazards. Formal examination of products has been more part of North American practice, but certainly the surgeon should ascertain that the major elements of the pregnancy are removed and are in keeping with the gestation of the pregnancy. With routine use of pre-operative ultrasound, suspicions of a non-viable pregnancy, ectopic pregnancy and hydatidiform mole should have been identified and appropriate clinical management instigated. For missed abortion and molar pregnancy, products should be sent for histopathology. Some centres may have protocols for examining tissue or subsequently tracking falling serum ~ hCG levels but other than in unusual cases, we find it sufficient to perform a further trans-vaginal scan in theatre to confirm interruption of the pregnancy. Failed attempted surgical abortion is recognized with a quoted failure rate of 2.3/ 1000 abortions from a large series under 12 weeks gestation.36 Failed evacuation is more likely if the patient is multiparous, if gestation is less than 6 weeks or when small cannulae are used. Sometimes this is explainable because there has been an unrecognized twin gestation or villi have been identified but the pregnancy not removed, or there is a uterine anomaly. Most failed surgical abortions in fact occur in patients with normal pelvic anatomy and where the operator is experienced. It is prudent to advise patients regarding the possibility and advise them to report any pregnancy symptoms persisting one week after the procedure so that evaluation for continuing pregnancy can take place and there can be early resort to further evacuation. Very rarely, even with full use of ultrasound, odd situations can arise, such as heterotopic pregnancy and it is important to be mindful of such things when clinical history and findings vary from the straightforward. Where there is any doubt about evacuation the patient must be followed up.

POST-OPERATIVE CARE

The majority of patients require only a short stay following a straightforward surgical termination. The stay needs to be slightly longer for patients who have had a general anaesthetic or intravenous sedation. All non-sensitized RhD negative women should be given anti-D IgG immunoprophylaxis following abortion. The recommended dose is 250 IU before 20 weeks gestationY After 20 weeks, 500 IU should be administered and testing undertaken for the size of feto-maternal haemorrhage to determine if additional anti-D is required. Before discharge women should be reminded to seek medical advice if they are concerned about pain, bleeding or a high temperature. Most units have some form of 24-hour telephone advice helpline available and have arrangements that allow for urgent clinical assessment and emergency gynaecological admission if required. Future contraception should be confirmed and the method initiated and/or appropriate supplies provided. Ovulation occurs within a month of first trimester abortion in over 90% of women.38 The patient should be provided with a discharge letter that gives details about the procedure and would allow a practitioner anywhere to get an immediate picture of the situation and deal with Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 9 of 15

Surgical abortion 255 complications. Formal counselling arrangements should be put in place for women with identified risk factors which could contribute to long-term post-abortion distress and who are agreeable. A 2-week follow-up appointment should be offered to each patient, either with the service provider or referring clinician but, in practice, default rates from these appointments are very high. Most immediate post-abortion complications will occur within this time scale. It is worth reminding patients that they can still contact the service for advice or counselling outwith formalised arrangements, and particularly in respect of seeking counselling support, there is no time limit.

SURGICAL ABORTION AFTER THE FIRST TRIMESTER

Late dilatation and evacuation (D& E) is practised extensively in the US and there are skilled practitioners in England, the Netherlands, France and parts of Australia. It is not widely performed in other parts of the world; for example in Scotland, mid- trimester terminations are almost exclusively undertaken using modern medical methods, and in England D & E has not found favour among NHS gynaecologists but is more widely used by the non-NHS abortion providers. Generally speaking, conventional first trimester surgical evacuation can be used up to 15 weeks gestation but thereafter specific techniques of cervical preparation and special instruments for D & E need to be used. Second trimester abortions entail more risk than earlier procedures. More modern methods of aggressive cervical preparation coupled with extensive clinical experience of the procedure have improved safety.39 The use of real-time ultrasound scanning during D & E can reduce perforation rates.40 In the 1970s prospective cohort studies comparing non-fatal complications showed clear advantages for D & E over instillation labour induction abortion. Major complication rates were twofold higher for instillation methods.41,42 Perforation occurred more frequently with D & E but haemorrhage, retained products and endometritis were more common with instillation methods. It was the view of the RCOG guideline development group that this procedure can really only be safely undertaken by gynaecologists who have been trained in the technique, have the necessary instruments to perform the procedure and have a clinical throughput adequate for maintenance of skills.' The technique requires an intensive and properly supervised training programme to achieve skills and competence in the procedure and this should be undertaken within units providing the service on a day-to-day basis. Thereafter, there has to be sufficient workload to maintain competency. For some patients it could be a welcome choice but meanwhile debate continues, in the absence of research evidence, as to which technique is most appropriate for terminating more advanced pregnancies.

COMPLICATIONS AND PROBLEMS

Legal abortion in developed countries is impressively safe. Sadly, illegal, remains a major contributor to maternal mortality on a global basis. The risk of complications is increased by older age, multiparity and increasing gestational age.43 Complications can be categorized into those which occur immediately at the time of the procedure or those which arise subsequently. Immediate complications are Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 10 of 15

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relatively infrequent so an operator could perform many procedures before encountering a problem. Complications relating to general anaesthesia can occur, but are beyond the scope of this chapter. Haemorrhage associated with abortion is not common and the RCOG guideline group reported this complication as 1.5/1000 abortions overall, taking their data from the England and Wales abortion statistics published in 1998.1 This can increase with advancing gestation and other risk factors identified include maternal age, parity, previous caesarean delivery, uterine fibroids and past history of post-abortion or post- partum bleeding.44 If blood loss is greater than 500 ml, intravenous fluids should be commenced and a check made to exclude cervical laceration, perforation, retained products or atonic uterus. For more substantial blood loss without apparent cause it would be prudent to keep the patient overnight and check haemoglobin level the following day. Blood transfusion might be required. Very rarely there could be intractable bleeding requiring intensive resuscitation and monitoring with consider- ation of internal iliac ligation or, more radically, hysterectomy. Coagulation status needs to be checked early and monitored in cases of major haemorrhage. Tears on the cervix are usually caused by instruments attached to the cervix or result from stretch-induced injury to the cervix. The advantages of cervical priming in reducing this risk have already been outlined. The problem should be particularly suspected where serious recurrent bleeding occurs after abortion despite a firmly involuted uterus. Cervical injury is more frequent and more serious with D & E in the second trimester. A review of seven published, large case-series by the RCOG guideline group revealed a 100-fold variation in the rate of cervical injury for first trimester vacuum aspiration, highlighting the difficulty of definition of cervical injury and variable data collection.19,45-50 Overall the rate of cervical injury was no greater than 1%for first trimester vacuum aspiration. Applying sponge forceps to compress the site can be useful to stop bleeding and surgical suturing might be required. There are some reports of hysteroscopy for diagnostic and therapeutic purposes when bleeding is controlled. High extending cervical tears are reported sometimes associated with intraperitoneal bleeding and pelvic haematoma and are obviously more complicated to manage and can require laparotomy. Uterine perforation rates are highest in teaching settings and more likely in women of higher parity or later gestation.48 Perforations should be suspected when instruments pass further than expected with a lack of resistance being perceived. Excessive bleeding can occur or the operator may be aware of a loss of feeling of the gritty surface of the endometrium. If either bowel or omentum is seen there is no doubt as to the problem. Perforation rates between I and 4/ I000 are reported in the large case-series reviewed for the RCOG guideline document.18,45,49-54 While admittedly some do imply that a conservative approach would be satisfactory for so-called 'benign perforation' (midline perforation without suction), UK practice would view the potential consequences resulting from visceral damage to be so serious that as a minimum laparoscopy would be required to confirm whether or not there was a perforation. Certainly, where there is any possibility or suspicion of bowel injury, formal surgical laparotomy with checking of bowel should be undertaken. Acute medical events, such as vasovagal reaction, anaphylaxis, asthmatic reactions and seizures can all occur at the time of abortion. Early complications following abortion include failure to remove the pregnancy with ongoing pregnancy and has been discussed. Where failed abortion is recognized during the first few weeks, most patients choose to undergo repeat suction curettage. A Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 11 of 15

Surgical abortion 257 patient electing to proceed with her pregnancy after failed abortion raises questions of subsequent risk to the woman and the fetus. Data are limited but miscarriage, premature rupture of membranes, chorioamnionitis, intra-uterine growth retardation, malformations and normal births have all been reported after failed surgical abortion.55-58 Retained products occur more commonly and usually the patient re- presents with cramp, lower abdominal pain and bleeding in the week following termination. Ultrasound usually reveals a heterogeneous mixed echo complex within the uterus, although it can be difficult to distinguish between retained products and blood clots. Small amounts of retained products can in fact pass spontaneously thus avoiding the need for any further intervention but, if substantial amounts of tissue are left, there is a risk of bleeding and infection and these cases are best managed with vacuum re-aspiration. There does not seem to be evidence regarding antibiotic prophylaxis for re-evacuation. Pelvic infection and endometritis may occur but risk is minimized by policies for antibiotic prophylaxis and/or infection screening and treatment. Typical signs and symptoms of post-abortion infection present in the first 3 or 4 days and any combination of pelvic pain, fever, pelvic tenderness and raised white blood count can occur. Swabs should be sent for culture and sensitivity and antibiotic treatment initiated. Complex emotional feelings are often experienced and include anger, guilt and regret contributing to short-term emotional distress.

FUTURE REPRODUCTIVE HEALTH

The bulk of evidence would support that abortion is a very safe procedure with few long-term problems. However patients do have concerns, usually because of a lack of information or worse still, misinformation. Pelvic infection or requirement for laparotomy associated with aQortion would, of course, be of potential risk for tubal damage. There is not any proven association between legal induced abortion and subsequent fertility difficulty.59-61 Published literature regarding an association with pre-term birth is conflicting, with earlier studies suggesting no effect but more recent studies showing a positive link.62-64Published studies have not been prospective and have not been able to control for competing risk factors, such as smoking or exposure to STls which might overestimate the impact of induced abortion on poor repro- ductive outcomes. Retrospective studies are flawed by selective recall, as women are often reluctant to reveal an abortion history, although those with a poor pregnancy outcome may' be more likely to mention a previous abortion. There is no prospective series which has considered miscarriage, mid-trimester loss and pre-term births. Hall and colleagues are curently reviewing this in Aberdeen. The impact of more recently introduced early medical abortion methods also requires to be considered, although it is not thought likely that medical abortion would increase the risk to subsequent reproductive health as it is relatively non-interventionist.

CONCLUSION

Legal, surgically induced abortion is one of the safest procedures in medicine. As with any other procedure, complications and failure are not completely avoidable, but they can be minimized by careful attention to detail at the pre-screening visit and with careful medical and surgical practice based on available published evidence and guidelines. Gestation should be accurately assessed and sound aseptic technique used Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 12 of 15

258 G. M. Flett and A. Templeton

for the abortion procedure. Clinicians should be experienced and comfortable with the procedures which they perform. There must be a high index of suspicion for possible complications and the patient must have ready access to clinical services for post-abortion advice and management of complications.

SUMMARY

Surgical abortion is safe, effective and necessary. The choice of abortion methods continues to extend with new developments in medical termination across all gestations and with renewed interest in early MVA and local anaesthetic techniques. MVA and medical termination have not been formally compared in trials. Likewise

Practice points • healthcare professionals should be aware of choices for abortion methods and women should receive information which helps them to choose a method which is right for them • women should have clinical pre-assessment and access to counselling support • ultrasound scanning pre-abortion is useful • cervical priming facilitates cervical dilatation and reduces risk for certain complications • antibiotic prophylaxis reduces short-term infective morbidity and should be offered as a minimum but a screen-and-treat policy for infection is an alternative; both together might confer even greater health advantage • aseptic technique should be observed for surgical abortion with careful and gentle instrumentation to avoid injury to cervix or uterus • practitioners should be specifically trained, competent and comfortable with the procedures they provide • dilatation and evacuation needs specific training and requires special cervical preparation and instruments • early pregnancy MVAneeds specific training and adherence to strict protocols to confirm complete evacuation • contraception should be available to start immediately following termination • patients must have access to services for post-abortion advice and management of complications

Research agenda • comparison of early MVA and medical termination with mifepristone and prostaglandin • comparison of late D & E and modern mid-trimester medical termination with mifepristone and prostaglandin • comparison of general .md local anaesthetic techniques for surgical abortion • prospective studies on the influence of medical and surgical termination on future reproductive health (fertility and obstetric outcomes) Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 13 of 15

Surgical abortion 259 there is no comparative trial evidence of late D & E against modern methods of mid- trimester medical termination. Debate continues regarding appropriate techniques for terminating more advanced gestation pregnancy. Practitioners should be specifically trained, competent and comfortable with the abortion methods which they provide. Clinical pre-assessment, counselling and informed choice form the basis of good practice. Ultrasound is useful but there is no randomized trial evidence of its value. As a minimum, antibiotic prophylaxis should be given to cover chlamydia and bacterial vaginosis and reduce infective complications. Infection screening and treatment provides wider public health gain through contact tracing and treatment to reduce re- infection risk. Cervical priming reduces the risk of cervical injury, uterine perforation, haemorrhage and incomplete evacuation. Mifepristone, gemeprost and misoprostol are all effective pharmacological priming agents. Unlicensed misoprostol has the advantage of low cost. Sound aseptic surgical technique is essential. There are no fully randomized studies comparing local and general anaesthesia and there are no controlled trials for greater or lesser cervical dilatation in first trimester surgical abortion. Oxytocics are not routinely administered. Complication rates are low and include haemorrhage, uterine perforation, cervical injury, failed abortion/ongoing pregnancy, retained products and post-abortion infection. There is no proven association between induced abortion and subsequent fertility difficulty or pre-term delivery but prospective studies are lacking.

REFERENCES

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16. Forman A, Ulmsten U, Banyai J et al. Evidence for a local affect of intercervical prostaglandin E2-gel. American Journal of Obstetrics and Gynecology 1982; 8: 456-462. 17. Grimes DA & Cates W. Complications from legally induced abortion; a review. Obstetrics and Gynecology Survey 1979; 34: In-191. 18. Grimes DA, Schulz KF & Cates W Jr. Prevention of uterine perforation during curettage abortion. Journal of the American Medical Association 1984; 251: 2108-2111. 19. Schultz KF, Grimes DA & Cates W Jr. Measures to prevent cervical injury during suction curettage abortion. Lancet 1983; I: 1182-1184. 20. EI-Refaey H, Calder L, Wheatley DN & Templeton A. Cervical priming with prostaglandin analogues, misoprostol and gemeprost. Lancet 1994; 343: 1207-1209. 21. Lawrie A, Penney G & Templeton A. A randomized comparison of oral and vaginal misoprostol for cervical priming before suction termination of pregnancy. British Journal of Obstetrics and Gynaeco/ogy 1996; 103: 1117-1119. 22. World Health Organization. The use of mifepristone (RU486) for cervical preparation in 1st trimester pregnancy termination by vacuum aspiration. British Journal of Obstetrics and Gynaecology 1990; W: 260-266. 23. Henshaw RC & Templeton AA. Pre-operativecervical preparation before 1st trimester vacuum aspiration: a randomized controlled comparison between gemeprost and mifepristone (RU486). British Journal of Obstetrics and Gynaecology 1991; 98: 1025-1030. 24. Ngai SW, Yeung KC, Lao T & Ho Pc. Oral misoprostol versus mifepristone for cervical dilatation before vacuum aspiration in first trimester in nulliparous pregnancy: a double blind prospective randomized study. British Journal of Obstetrics and Gynaeco/ogy 1996; 103: 1120-1123. 25. Radestad A, Bygdeman M & Green K. Induced cervical ripening with mifepristone (RU486) and bioconversion of arachidonic acid in human pregnant uterine cervix in the first trimester. Contraception 1990; 41: 283-292. 26. Carbonne B, Brennand JE, Maria B et al. Effects of gemeprost and mifepristone on the mechanical properties of the cervix prior to first trimester termination of pregnancy. British Journal of Obstetrics and Gynaeco/ogy 1995; 102: 553-558. 27. Ashok PW, Flett GM & Templeton A. Mifepristone versus vaginally administered misoprostol for cervical priming before first trimester termination of pregnancy: a randomized, controlled study. American Journal of Obstetrics and Gynecology 2000; 183: 998-1002. 28. Fong YF, Singh Kuldip & Prasad RNV. A comparative study using two dose regimens (200 Jlg and 400 Jlg) of vaginal misoprostol for preoperative cervical dilatation in first trimester nulliparae. British Journal of Obstetrics and Gynaeco/ogy 1998; 105: 413-417. 29. Henshaw FK & Van Vort J. Abortion services in the United States, 1991 and 1992. Family Planning Perspectives 1994; 26: 100-1 12. 30. Grimes DA, Cates W Jr & Selik RM. Abortion facilities and the risk of death. Family Planning Perspectives 1981; 13: 30-32. 31. De-Jonge ETM, Pattison RC, Makin JD & Venter CPo Is ward evacuation for uncomplicated incomplete abortion under systemic analgesia safe and effective? A randomized clinical trial. South African Medical Journal 1994; 84: 481-483. 32. MacKay HT, Schulz KS & Grimes DA. Safety of local versus general anaesthesia for second trimester dilatation and evacuation abortion. Obstetrics and Gynecology 1985; 66: 661-665. 33. Grimes DA, Schulz KF, Cates W Jr & Tyler CWo Local versus general anaesthesia: Which is safer for performing suction curettage abortion. American Journal of Obstetrics and Gynecology 1979; 135: 1030-1035. 34. Garrioch DB, Gilbert JR & Planteuin OM. Choice of ecbolic and the morbidity of day case terminations of pregnancy. British Journal of Obstetrics and Gynaecology 1988; 88: 1029-1032. 35. Ali PB & Smith G. The effect of syntocinon on blood loss during first trimester suction curettage. Anaesthesia 1996; 51: 483-485. 36. Kaunitz AM, Rovira EZ, Grimes DA & Schulz KF.Abortions that fail. Obstetrics and Gynecology 1985;66: 533-537. 37. Robson S & RCOG-Royal College of Obstetricians and Gynaecologists. Use of anti-D Immunoglobulin for Rhesus Prophylaxis. London: RCOG, 1999. 38. Cameron IT & Baird DT. The return to ovulation following early abortion: a comparison between vacuum aspiration and prostaglandin. Acta Endocrino/ogica 1988; 118: 161-167. 39. Lawson HW, Frye EA, Atrash HK et al. Abortion mortality, United States, 19n through 1987.American Journal of Obstetrics and Gynecology 1994; 171: 1365-13n. 40. Darney P & Sweet L. Routine intraoperative ultrasanography for 2nd trimester abortion reduces inci- dence of uterine perforation. Journal of Ultrasound Medicine 1989; 8: 71-75. Case: 3:13-cv-00465-wmc Document #: 245-6 Filed: 06/11/14 Page 15 of 15

Surgical abortion 261

41. Kafrissen ME, Schulz KS, Grimes OA et al. Mid trimester abortion; Intra-amniotic installation of hyperosmolar urea and prostaglandin F2 lX versus dialatation and evacuation. Journal of the American Medical Association 1984; 251: 916-919. 42. Wadhera S & Millar WJ. Second.trimester abortions: trends and medical complications. Health and Reproduction 1994; 6: 441-454. 43. Bachlor JW, Schulz KF, Grimes OA & Hogue CJ. The risk of serious complications from induced abortion: do personal characteristics make a difference? American Journal of Obstetrics and Gynecology 1985; 153: 14-20. 44. Grimes OA, Kafrissen ME, O'Reilly KR et al. Fatal hemorrhage from legal abortion in the United States. Surgery Gynecology and Obstetrics 1983; 157: 461-466. 45. Andolsek L, Cheng M, Hren M et al. The safety of local anaesthesia and outpatient treatment: a controlled study of induced abortion by vacuum aspiration. Studies in Family Planning 19n; 8: 118-124. 46. Ferris L, McMain -Klein & Colodorey N. Factors associated with immediate abortion complication. Canadian Medical Association Journal 1996; 154: 16n-I685. 47. RCGP & RCOG. Joint study of the Royal College of General Practitioners and the Royal College of Obstetricians and Gynaecologists. Induced abortion operations and their early sequela. Journal of the Royal College of General Practitioners 1985; 35: 175-180. 48. Jacot FR, Poulin C, Bilodeau AP et al. A five year experience with second trimester induced abortions: no increase in complication rate as compared to the first trimester. American Journal of Obstetrics and Gynecology 1993; 168: 633-637. 49. Hakim-Elahi E, Tovell HM & Burnhill MS. Complications of first trimester abortion: a report of 170,000 cases. Obstetrics and Gynecology 1990; 76: 129-135. SO. Heisterberge L & Kringelbach M. Early complications after induced first trimester abortion. Acta Obstetricia et Gynecologica Scandinavica 1987; 66: 201-204. 5 I. King TM, Atienza MF & Burkman RT. The incidence of abdominal surgical procedures in a population undergoing abortion. American Journal of Obstetrics and Gynecology 1980; 137: 530-533. 52. Hodgson JE & Portmann KC. Complications of 10,453 consecutive first trimester abortions: a pros- pective study. American Journal of Obstetrics and Gynecology 1974; 120: 802-807. 53. Nathanson BN. Ambulatory abortion: experience with 26,000 cases. New England Journal of Medicine 19n; 286: 403-407. 54. Beric BM & Kupresanin M. Vacuum aspiration, using pericervical block, for legal abortion as an out patient procedure up to the 12th week of pregnancy. Lancet 1971; 2: 619-621. 55. Fielding WL, Lee SY & Friedman EA. Continued pregnancy after failed first trimester abortion. Obstetrics and Gynecology 1978; 52: 56-58. 56. Ricciotti HA, Calayag PT, Abbott J et al. Obstetric outcome after failed termination of pregnancy - a report of two cases. American Journal of Obstetrics and Gynecology 1995; 173: 1619-1620. 57. Arnon J & Ornoy A. Clinical teratology counseling and consultation caSe report: outcome of pregnancy after failure of early induced abortion. Teratology 1995; 51: 120-122. 58. Holmes LB.The potential teratogenicity of a 0 & C when pregnancy continues. Teratology 1992;45: 446. 59. Daling JR, Spadoni LR & Emanuel I. Role of induced abortion in secondary infertility. Obstetrics and Gynecology 1981; 57: 59-61. 60. Oaling JR, Weiss NS, Voigt L et al. Tubal infertility in relation to prior induced abortion. Fertility and Sterility 1985; 43: 389-394. 61. Hernadi Z, Smid 1 & Lampe L. Impact of pregnancy termination on subsequent fertility. Acta Medica Hungarica 1986; 43: 155-160. 62. Hogue CJ & Cates W Jr. The effect of induced abortion on subsequent reproduction. Epidemiologic Reviews 1982; 4: 66-94. 63. Atrash HK & Hogie CJ. The effect of pregnancy termination on future reproduction. Bai/liere's Clinical Obstetrics and Gynaecology 1990; 4: 391-405. 64. Lumley J. The epidemiology of pre term birth. Bailliere's Clinical Obstetrics and Gynaecology 1993; 7: 4n-498. Case: 3:13-cv-00465-wmc Document #: 245-7 Filed: 06/11/14 Page 1 of 3 (

ISRAEL J. MED. SeL PR.E.LIMINARY AND SHORT COMMUNICATIONS

Arab couples and the findings therefrom can consti- 6. Luciano AA, Peluso J, Koch ill, Maier D, Kuslis S, Davi- son E. Temporal relationship and reliability of the clinical, tute a base for a population study. hormonal and ultrasonographic indicies of ovulation in in- fertile women. Obste/ Gynecoll990;75:412-416. SHLOMO EUY AHU MOSHE BEN-AMI 7. Glezerman M, BarlOOv B. Semen analysis. In: Insler V, Lunenfeld B, eds. Infertility, male and female. New YOlk: MICHAELZIV EHUDWEINER Churchill Livingstone, 1986:243-271. EUEZER SHALEV 8. Insler V. Investigation of the infertile couple' (fertility survey) and organization of the infertility clinic. In: Insler DepartmenJs of Obstetrics and Gynecology. CenJral Emek V, Lunenfeld B. eds. Infertility: male and female: New Hospital, Afula, Israel York: Churchill Uvingstone, 1986:697-723. 9. Snowden EU, Jarrell JC, Dawood MY. Comparison of diagnostic accuracy of laparoscopy, hysteroscopy and hysterosalpingography in evaluation of female infertility. Fer/if S/eriI1984;41:709-713. REFERENCES 10. Moghissi KS, Wallach EE. Unexplained infertility. Ferril J. Speroff Z. Glass RH, Kase NG. Clinical gynecological SleriI1963;39:5-12. endocrinology and infertility, 4th ed. Baltimore: Williams 1I. Bronson R, Cooper G, Rosenfeld D. Sperm antibodies, and Wilkins, 1994:80&-839. their role in infertility. Fer/if S/eril 1984;42(2): 171-183. 2. Jaffe SB, Jewelewicz R. The basic infertility investigation. 12. Westrom L. Effect of acute pelvic inflammatory disease on Ferlil S/eriI1991;56:599-613. infertility. Am] Obsle/ GynecoI1975;121:707-713. 3. Jacobs LA. Initial clinical survey of the infertile couple. Prim Care 1988;15(3):575-593. 4. World Health Organi,zation. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction, 2nd ed. Cambridge: University of Cambridge, 1992:13-27. Address for correspondence: Dr. E. Shalev, Department of 5. McCarthy II, Rockelle HE. Prediction of ovulation with Obstetrics and Gynecology, Central Emek Hospital, 18101 basal body temperawre. f Report Med 1986;31 (Supp! Afula, Israel 8):742-747.

MANAGEMENT OF UTERINEPERFORATION COMPLICATING FIRST-TRIMESTER TERMINA nON OF PREGNANCY

Isr J Med Sci 1995;31:232-234

Keywords: abortion complication; diagnostic laparoscopy; laparotomy

First-lTimester termination of pregnancy is a common in delay in diagnosis and in control of significant procedure in gynecological practice. Uterine perfora- bleeding, which may prove to have serious conse- tion is a serious complication of this procedure, the quences. Many authors recommend immediate lapa- major dangers of. perforation being inlTaabdominal roscopy 10 assess the uterine injury and to enable bleeding and bowel lacerations. The published inci- completion of uterine evacuation under laparoscopic dence of uterine perforation varies between 0.8 and control. Also, bowel injury can be assessed during la- 6.4/1000 procedures (l,2), although the true iilcidence paroscopy (4,6,7). Immediate laparotomy is advocat- is probably underestimated (3-5). ' ed if bowel or omentum is extruding from the cervix, The management of uterine perforation remains if severe bleeding from pelvic viscera is diagnosed, controversial. It may include expectant management, and if the patient is hemodynamically unstable (1,7). laparoscopy, or laparotomy. Expectant management The management of uterine perforation in differ- entails close observation of the patient for early signs ent series is shown in Table 1. Of the 122 cases pre- of hemorrhage (3): However, this approach may result sented, 86 (70%) were managed by laparoscopy or

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T.MED.ScL VOL.31,NO.4, APRll.1995 is S, Davi. le clinical, laparotomy, and 36 (30%) were managed conserva- 2.5 years, range 0.9-4.6 years) and under general .lion in in. tively (1,3,4,6,7). anesthesia. DILAPAN@ (Gynotech Inc., USA) Or Our current policy is to perform diagnostic lapa- laminana japonicum was inserted into the cervical ca- Insler V, roscopy in all cases of suspected uterine perforation. nal 12 h prior to the procedure in primigravidas only. lew York We have analyzed our experience with uterine perfo- Products of conception were aspirated by a plastic , (fenility rations in order to assess the necessity for surgical cannula after gradual dilatation of the cervix with He- In: Insler approach in these patients. . gar dilators. Sharp curettage was subsequently done to nile: New ensure that the uterine cavity was empty. When perforation was suspected, the procedure 'anson of MATERIAL AND METHODS :opy and was discontinued and consultation was requested from nfenility. Between January 1983 and December 1992, 4,688 an attending senior gynecologist. If the diagnosis of first-trimester pregnancy terminations were performed perfo'ration was confirmed by sounding, diagnostic ty. Ferlil in our department. The patients were referred for the laparoscopy was immediately performed. Further procedure after confirmation of the pregnancy by a operative procedures were performed according (0 the IUbodies, -183. positive pregnancy test and gynecological examina- laparoscopic findings. iseaseon tion, and approval of its termination by a special com. mittee in accordance with the requirements of Israeli law. During this 3 year period all patients had an ultra- RESULTS sonographic examination demonstrating an intraute- The rate of uterine perforation was 2.6/1 ,000 rine pregnancy with positive heart beats prior to procedures. The mean age of the patients was 33.6 operation. All procedures were carried out by years (range 20-42) and mean parity 3.4 (range 2-6). nenlof residents (mean practical gynecological experience The mean gestational age was 7.9 menstrual weeks 18101 Table 1. Management of uterine perforalion

No. of Laparotomy uterine Laparoscopy Suturesof Repairof Author(Ref.) perforations Conservative Diagnostic Cauterization uterus bowelinjury Hysterectomy

Kaaliet at. (3)' 10 8 2 Mittaland Misra (4) 37 3 2 31 3 Lauersenand Birnbaum(7) 11 6 4 Nathansoo(I) 24 13 10 2b 1 Freimanand Wulff (6) 28 12 4 4 3 7 Presentseries 12 3 3 6

Total 122 36 17 4 55 8° 9

'Cases of unsuspectedperforatioosdiscoveredduringlaparoscopicstetilizauonswerenot included. bpaltialomentectomy. CCoocomitantsutureof uterus (6 cases)and hysterectomy(I case). 2-234, Table 2. First-trimester termination of pregnancy

Case Age Perforating no. (yr) Parity Weeks instrument Management

::ant I 36 4 6 Unknown Laparoscopy- nse. 2 35 6 8 Unknown perforationsite small tpa- 3 39 4 8 Unknown and no! bleeding lble lpic 4 33 3 9 Unknown Laparoscopy- la. 5 42 2 6 Unknown bleedingat perforation 6 ;at- 39 5 8 Unknown sitecauterized ,ix, 7 20 2 7 Unknown Laparotomy- ed, 8 26 2 j Cannula suture of ). 9 22 2 8 Cannula perforatioo er- 10 40 5 8 Curette afteridentifying re- 11 37 6 8 Unknown active bleeding or 12 35 3 10 Unknown at laparoscopy

233

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ISRAEL 1. MED. SCI. PRELNc;ARY AXD SHORTCOMML"NICATIONS

(range 6-10). Half of the patients had delivered or sels, creation of subcutaneous emphysema, or electri- aborted within 1 year before the procedure. cal bowel injuries, have an overall incidence of 1.87% In nine (75%) cases, the offending instrument on analysis of 32,719 laparoscopies (8). Currenl1y, la- causing the perforation could not be identified. There paroscopy is a safe tcchnique and we thus recommend was no correlation between uterine position and site of this procedure in all cases of uterine perforation since perforation. In five cases completion of uterine evacu- the risk of a positive finding requiring immediate sur- ation under laparoseopic guidance was necessary. The gical measures is between 50% (1,3,4,6,7) and 75% management of these patients is described in Table 2. (current study) versus a very small risk of a laparos- In three cases only diagnostic laparoscopy was neces- copic complication of 1.8%. In our study 50% of per- sary, in three patients cauterization of uterine bleeders forations were eventually subjected to laparotomy, but was performed via laparoscopy, and in the remaining with the new laparoscopic surgical equipment it is an- six, laparotomy was done in order to repair uterine ticipated thal most cases could be managed by this lacerations. In the present series, one patient only (no. modality. 7) required blood transfusion. No bowel injury was found in this series. All patients had an uneventful postoperative recovery. REINALDO GOLDCHMIT YARON ZALEL URIEL ELCHALAL AVIMATZKEL RAM DGANl DISCUSSION The incidence of uterine perforation (2.6/1,000 proce- Department 0/ Obstetrics and Gynecology. Kaplan Hospital. dures) found in the present study is similar to that de- Rehovot (affiliated to Hebrew University-Hadassah Medi- scribed in previous studies. Advanced age, parity, ges- cal School, Jerusalem). Israel tational age below 8 weeks, and recent delivery or abortion have been associated with increased inci- dence of uterine perforation (4,6,7). Laminaria may play an important role since all cases of uterine perfo- REFERENCES ration occurred without its use. J. Nathanson BN. Management of uterine perforations suf- Various authors reported a variety of approaches fered at elective abortion. Am J Obstet GYlU!col 1972;114: to the management of uterine perforations (Table 1). . 1054-1059. 2. Mobetg PJ. l:terine perforations in connection with According to Kaali et al. (3), following perforation, vacuum aspiration in legal abortion. In! J Gynoecol Obstet curettage can be completed under sonographic guid- 1976;14:77-79. ance, if necessary. They described 10 cases of uterine 3. KaaJi SG. Szigetvari lA, Bartfai GS. The frequency and perforations that were so managed without further management of uterine perforations during first trimester abortions. AmJ Obstet GynecoI1989;161:406-408. complication. Freiman and Wulff (6) managed 43% of 4. Miual S, Misra SL. Uterine perforation following medical their patients conservatively and suggested this option termination of pregnancy by vacuum aspiration. In! J in midline uterine perforations if the evacuation has GynaecolObstel 1985;23:45-49. been completed. At variance with the previous au- 5. White MK, Ory HW, Goldenberg LA. A case control study thors, Lauersen and Birnbaum (7) suggested that all of uterine perforations documented at laparoscopy. Am J Obstet GynecoI1977;129:623-625. patients with uterine perforations should undergo lapa- 6. Freiman SM, Wulff GJL Jr. Management of uterine roscopy. Laparoscopy is advocated in all cases of ute- perforation following elective abortion. Obstet Gynecol rine perforations for several reasons: intraperitoneal 1977;50:647-650. bleeding may be profuse and external bleeding may be 7. Lauersen NH, Birnbaum S. Laparoscopy as a diagnostic and therapeutic technique in uterine perforations during minimal, especially if the perforation is in the lateral first trimester abortions. Am J Obstet GYlU!col 1977;117: uterine wall. Furthermore, bowel injury may be identi- 522-526. fied if vacuum suction, sharp curette or ovum forceps 8. Loffer FD, Pent D. Indications, contraindications and were used. complications of laparoscopy. Obstet GYlU!colSurv 1975; 30:407-42 J. The data in our series support the need for laparos- copic management, and confirm the conclusions reached by others (4,7). Three-fourths (9/12) of our patients were found to have inlraabdominal bleeding that necessitated hemostatic measures: three by lapa- roseopy and six by laparotomy (Table 2). Address for correspondence: Dr. R. Goldchmit, Deparunent Laparoscopy is not free of complications. Compli- Df ObstelIics and Gynecology, Kaplan Hospital, 76100 cations, such as penetration of a viscus or blood ves- Rehovot, Israel.

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CLINICAL OBSTETRICS AND GYNECOLOGY Volume 52. Number 2.198-204 (Q 2009, Lippincott Williams & Wilkins

Infectious Complications of Pregnancy Termination

LISA RAHANGDALE, MD, MPH Department of Obstetrics and Gynecology, Stanford University, Stanford, California

Abstract: Infectious complications are a significant operative injury or retained products of source of morbidity and mortality associated with conception (RPOC). Infection is usually pregnancy termination worldwide. However, in areas polymicrobial but has been associated where abortion practices are legal, the risk of infection is very low. Proper technique, prophylaxis, and initial with endogenous vaginal flora (eg, group management of septic abortion have led to a signifi- B ~-hemolytic streptococci, Bacteriodes cant decrease in risk of serious complications such as fragilis, Escherichia coli, Staphylococcus sepsis and death. Clinical features, management, and aureus), preexisting infections such as prevention of postabortal infection will be reviewed in Neisseria gonorrhea, Chlamydia tracho- the setting of legalized abortion. Key words: septic abortion, infection, endometritis, matis, and Trichomonas vaginalis or sepsis, retained products of conception bacterial vaginosis (BV).1,2 There is in- creasing interest in the role of Mycoplas- ma genitalum in pelvic infection after abortion.3 Introduction Five cases of fatal toxic shock asso- Infection after abortion can lead to sig- ciated with Clostridium sordellii after nificant morbidity and mortality through medical abortion (mifepristone and miso- endometritis, peritonitis, and sepsis. prostol) and 2 cases of fatal toxic shock Though numbers of women presenting associated with Clostridium perfingens with septic abortion have decreased with after medical abortion (mifepristone and legalization of abortion procedures, wo- misoprostol, laminaria and misoprostol) men can present with infection after sur- have been reported. The connection gical or medical abortion secondary to between these organisms and medical abortion is unclear.4,5 C. perfingens has Correspondence: Lisa Rahangdale, MD, MPH, De- been associated with illegal abortion in partment of Obstetrics & Gynecology, Stanford Uni- the United States, whereas Clostridium versity, 300 Pasteur Dr HH333, Stanford. CA 94317. E-mail: [email protected] tetani (tetanus) is associated with septic 3 Funding Disclosures: None. abortion in developing countries. ,6,7

CLINICAL OBSTETRICS AND GYNECOLOGY I VOLUME 52 I NUMBER 2 I JUNE 2009

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Infections and Pregnancy Termination 199

Approximately 0.1-4.7% of surgical Clinical Features abortions worldwide are affected by uter- Women who develop septic abortion ine infection.8 A retrospective case series present with fever, lower abdominal pain, of 1,677 women who underwent manual and vaginal bleeding. Diagnosis can vacuum aspiration (MVA) in the office sometimes be delayed in women reluctant setting reported 0.7% of women were to divulge pregnancy history or in women diagnosed with infection; the majority of who have undergone illegal abortion. these MVAs were between 7 and 10 These women are frequently at higher risk weeks.9 Case reports of toxic shock syn- for infection that those undergoing legal drome have been reported in association abortion.6 Of note, misoprostol adminis- with laminaria placement.lo However, a tration has been associated with fevers up study evaluating bacteria associated with to 38°C in 30% to 50% of women; these laminaria removed before surgical abor- temperatures may persist up to 24 hours tion failed to correlate presence of typical after last misoprostol administration and infection-associated bacteria with a clin- are not necessarily a sign of infection. 15 ical outcome of infection. II Upon presentation to medical care, Despite the above-noted case reports of women of reproductive age with the fatal toxic shock associated with mifepris- above-noted symptoms should undergo tone-induced abortion, risk of death with urine or serum pregnancy testing and, if medical abortion is similar to surgical possible, a reproductive health history abortion and less than childbirth.12 A should be obtained confidentially. Ab- pooled analysis of 46,421 women in 65 dominal examination may show signs of studies on medical abortions up to 26 peritonitis with guarding and/or rebound weeks gestation reported that 0.9% of present. Pelvic examination should in- medical abortions were complicated by clude visual' inspection of the vagina and infection. Risk of infection was < 0.5% cervix for lacerations, cellulitis, bleeding, for medical abortion by mifepristone and pus, or products of conception (PaC). oral misoprostol, methotrexate and vagi- DNA tests or cultures for Chlamydia nal misoprostol, or vaginal misoprostol and Gonorrhea should be performed if alone; risk of infection with mifepristone they have not already been performed. and vaginal misopiostol and mifepristone Aerobic and anaerobic cervical cultures and gemeprost was 1.3% and 1.6%, re- should also be performed though most spectively.8 A case series of 1002 women results are polymicrobial. If pac are undergoing second-trimester abortion removed at this point or during curettage, with misoprostol reported a risk of infec- these should be sent for culture and Gram tion of3 in 1000.13 stain. Bimanual examination will reveal Risk of infection comparing manage- uterine or parametrial tenderness; crepi- ment strategies of medical abortion, tus in the pelvis is consistent with anaero- surgical abortion or expectant manage- bic gas production (ie, gas gangrene). ment has been evaluated in a randomized Vital signs may show signs of septic controlled trial of 1200women < 14weeks shock. gestation in the United Kingdom. It de- Laboratory testing may reveal a leuko- monstrated that there was no difference cytosis and diminished hemoglobin/ in incident infection within 14 days of hematocrit. Blood cultures may indicate follow-up between the management bacteremia. Ultrasound is useful to eval- options. None of these women received uate for RPOC, parametrial abscess or prophylactic antibiotics or were screened hematoma. Chest x-ray or abdominal/ for gynecologic infection before interven- pelvic x-ray may detect air in pelvic or- tions.14 gans or under the diaphragm in the case of

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200 Rahangdale

uterine perforation after surgical abor- exploration can be used to repair da- tion. Computed tomography scan or pel- maged blood vessels or organs such as vis is useful to evaluate for operative the uterus, bowel, or bladder. Hysterec- injury, abscess, or hematoma. tomy, in addition to oophorectomy, may Treatment of septic abortion includes be necessary if clostridial infection is sus- broad-spectrum antibiotic treatment of pected due to a dusky, discolored appear- endometritis, supportive management of ance to uterus, crepitus in pelvic tissue, or septic shock, removal of RPOC without radiologic findings such as air in the uter- delay, repair of any lacerations, or per- ine wall. Abscess and purulent material forations if necessary. Extensive infection should be drained and irrigated. Place- or injury to pelvic organs may require ment of drains, mass closure of the fascia, exploratory surgery and/or hysterectomy. and delayed primary closure should be considered in cases of severe infection.6 Endometritis/ Peritonitis Women presenting with septic abortion RPOC should be treated with intravenous broad Removal of RPOC should occur expedi- spectrum antibiotics immediately. Tradi- tiously regardless of the overall condition tionally, penicillin or ampicillin plus clin- of the patient. If RPOC are noted after a damycin and gentamycin have been first-trimester abortion, immediate re- recommended.6 However, as septic abor- moval of RPOC can occur using surgical tion is essentially a form of endometritis abortion techniques such as suction cur- or pelvic inflammatory disease, treatment ettage or MVA. In cases where RPOC are with regimens recommended for those noted in a medically stable patient, entities would also be reasonable. The 800 mcg misoprostol can be given per goal is to provide broad-spectrum anti- vagina or through a sublingual or buccal biotics to treat aerobic and anaerobic route. Cases of ongoing pregnancy due Gram-negative and Gram-positive bac- inadequate evaluation of evacuated con- teria secondary to the polymicrobial nat- tents after surgical abortion, multiple ge- ure of the infection. Alternative antibiotic stations where only 1 sac was removed, or choices for postoperative pelvic infeCtions failed medical abortion must be addressed include second and third generation with the individual patient for further cephalosporins such as cefoxitin, cefotax- management. The potential teratogenic ime, and ceftriaxone, and other classes effect ofmisoprostol should be addressed; of antibiotics including piperacillin, ticar- first-trimester misoprostol exposure has cillin/clavulanic acid, metronidazole, been associated with Mobius syndrome imipenim/cilastin, or levofloxacin. Indivi- [odds ratio 29.7; 95% confidence interval dual institutional nosocomial pathogens (CI), 11.6-76.0].16 or resistant organisms in the community If RPOC are from a second-trimester such as methicillin-resistant S. aureus pregnancy and the care provider lacks should be considered in severely ill or experience in techniques of second-tri- septic patients. mester abortion, medical management is Evaluation for and removal of RPOC necessary. Stubblefield and Grimes6 have should occur simultaneously to remove recommended the following: IS-methyl the source of infection and prevent further prostaglandin F2ex (carboprost trometha- complications and sepsis. Laparotomy mine) 250 j.tgintramuscularly every 2 to 3 may be necessary if a woman is acutely hours or high dose intravenous oxytocin. hemorrhaging or if there is no response to The recommended oxytocin regimen is removal of RPOC or antibiotics. Surgical 50 units of oxytocin in 500 mL of 5%

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.Infections and Pregnancy Termination 201

dextrose and normal saline given over 3 DIAGNOSIS OF RPOC hours followed by 1 hour of rest. This Digital examination consistent with a di- regimen can be repeated until abortion is lated cervix in the presence of bleeding complete or a total of 300 units of oxyto- during pregnancy can be a sign of incom- cin have been given. Prostaglandin E2 plete abortion. Ultrasound has become suppositories cause fever and are contra- heavily relied upon for diagnosis of indicated in septic patients. If these agents RPOC despite equivocal findings as the are not available, a large Foley catheter uterine cavity is rarely empty within 1 (50 mL balloon) with weighted traction week of abortion.I9 The presence of a may be placed in the lower uterus to dilate gestational sac is a clear indication of the cervix.6 RPOC. However, frequently ultrasound findings are not so obvious.20 A focal RISK FACTORS FOR RPOC echogenic mass can be a reliable sign of Traditionally, surgical abortion followed RPOC though a clot can appear similar. If by immediate inspection of specimen to no focal mass is present, endometrial confirm the presence of POC has been thickness can be evaluated. A natural recommended to avoid RPOC. Published assumption is that thin endometrium is literature supports the efficacy of surgical less likely to contain POC and a thick abortion (ie, suction curettage, MVA) in endometrium is more likely to contain complete removal of POC.14,17,lSA Co- POC; however, reliable parameters for chrane review of 5 trials (689 women) of measurement have not been determined. expectant management versus surgical RPOC have been present at endometrial abortion of spontaneous pregnancy losses thicknesses of < 5 mm though the clinical < 14 weeks gestation concluded a lower significance of such small RPOC is un- risk of infection [relative risk (RR = 0.29; known. Clinically significant cutoffs for 95% CI, 0.09-0.87] but higher risk of endometrial thickness have ranged from RPOC (RR = 5.37; 95% CI, 2.57-11.22) 8 mm to 20 mm.20 A prospective study of with expectant management. The need for 52 women with a clinically incomplete subsequent surgical evacuation of the abortion found that only 50% had uterus was increased in the expectant RPOC. The sensitivity and specificity of management group (RR = 4.78; 95% digital cervical exam for determining CI, 1.99-11.48),17In addition, a random- RPOC were 65% and 56%, respectively. ized controlled trial of 1200 women with The sensitivity and specificity of a trans- miscarriages at < 14 weeks gestation de- vaginal uitrasound measurement of monstrated that there were significantly < 8 mm bilayer endometrial thickness more unplanned surgical curettages after were 100% and 80%, respectively. 19 medical management or expectant man- Endometrial thicknesses of < 8 to 10mm agement compared with surgical abor- with no focal mass in the endometrium tion. However, there was no difference have been reported as clinically signifi- in incident infection between the 3 groups cant for ruling out RPOC.19-21 within 14 days follow-up.14 Of note, sys- Doppler ultrasound can be another tematic review comparing elective va- useful tool to assess focal masses and cuum aspirations versus manual vacuum thickened endometrium in suspected aspirations at < 12 weeks found no sig- RPOC. Theoretically, Doppler flow will nificant difference in likelihood of be more likely within RPOC compared complete abortion (97.5% vs. 97.9%; with blood clot. However, parameters for RR = 1.0; 95% CI, 0.99-1.02; P = 0.66) Doppler flow measurement have not in a pooled analysis of 5 randomized been consistent in research studies and, controlled trials. IS therefore, it is difficult to assess clinical

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202 Rahangdale

significance. 19,21Case reports of RPOC specialists for appropriate cardiovascular mimicking arterio-venous malformations support. on Doppler ultrasound and MRI have Toxic shock syndrome is a form of been reported.22 sepsis caused by exotoxins released by Ultrasound has also been reported as a bacteria such as S. aureus, Group A Strep- tool to prevent RPOC during surgical tococcus or Clostridium species. It is char- abortion. A randomized controlled trial acterized by acute onset of fever, chills, comparing the use of ultrasound during vomiting, diarrhea, myalgias, and skin surgical first-trimester abortion of 330 rash which can progress to refractory women showed a significant difference in hypotension and multiorgan failure. Of need for antibiotics within I week of the note, the 4 cases of C. sordellii infection procedure (P = 0.005) and need for repeat associated with medical abortion in the evacuation for RPOC (P = 0.023).23 A United States had unusual presentations in randomized controlled trial of assessment that the women presented without fever. of uterine cavity immediately after surgical However, all had tachycardia, refractory abortion between 7 and 14weeks gestation hypotension, ascites, hemoconcentration, in.809 women found no cases of eventual and markedly elevated leukocytosis consis- RPOC in women with endometrial thick- tent with toxic shock syndrome.4 nesses of < 8 mm. Sensitivity and specifi- city for RPOC at > 8 mm was 100% and 99.1%, respectively. Positive predictive Prevention of Infection value and negative predictive value were Primary prevention of septic abortion is 85.7% and 100%, respectively.24 In set- based on providing women with access to tings where ultrasound is readily available, contraception and safe and accessible it may be a useful tool to evaluate complete abortion services.6 There are no data to removal of POC. support use of antibiotic prophylaxis for medical abortion.12 However, antibiotic prophylaxis is recommended in women Sepsis undergoing surgical abortion.25,26 The Signs of sepsis include hypo- or hy- rate of postabortal endometritis can be perthermia, tachycardia, tachypnia, and reduced by42% in the setting of antibiotic hypotension. In women presenting with prophylaxis.26 A meta-analysis of 12 stu- these findings, supportive therapy should dies conducted between 1966 and 1994 be initiated in addition to antibiotics and comparing antibiotic prophylaxis versus removal of RPOC. Persons with severe placebo in women undergoing suction sepsis also can present with metabolic curettage at < 16 weeks gestation showed acidosis, acute encephalopathy, oliguria, that antibiotic prophylaxis was beneficial hypoxemia, and disseminated intravascu- in preventing postabortion infection. lar coagulation in response to a systemic Summary RR was 0.58 (95% CI, 0.47- inflammatory response. These findings 0.71) for antibiotics overall. When groups may progress to septic shock with severe were stratified into high-risk, low-risk hypotension leading to altered organ per- low-incident populations, a statistically fusion-hypoxia, elevated lactate levels, significant risk reduction was still seen.26 altered mental state, and oliguria. Keys to Exact dosing and antibiotic choice for prevention of sepsis and shock are early prophylaxis is uncertain. In the above- recognition of an infectious complication noted meta-analysis, statistically signifi- of abortion, expeditious supportive ther- cant risk reduction was seen with different apy, correction of coagulation abnormal- classes of antibiotics: tetracycline (doxy- ities, and consultation with intensive care cycline, lymecycline) and nitroimidazoles

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Infections and Pregnancy Termination 203

(tinidizole, metronidazole).26 A regimen abortion procedures need to be evaluated of 100 mg doxycycline orally I hour be- and treated expeditiously to avoid com- fore the procedure and 200 mg orally after plications of endometritis, sepsis, and the procedure showed that antibiotic pro- RPOc. Ultrasound can be a useful tool phylaxis was also cost-effective, preventing to evaluate for RPOC, though clinical 6500 cases of postabortion infection and significance of ultrasound findings is de- saving over $600,000 annually.26 More bated. Antibiotic prophylaxis is effica- recently, a regimen of flouroquinolone cious and cost-effective, and, therefore, (prulifloxacin) antibiotic prophylaxis should be standard practice for women started 1 day prior and continued 2 days undergoing surgical abortion procedures. after abortion showed a statistically signif- icant benefit compared with flouroquino- lone prophylaxis started after procedure.27 References Treatment of BV before first-trimester 1. Stevenson MM, Radcliffe KW. Prevent- suction curettage has shown mixed results ing pelvic infection. after abortion. Int J in terms of preventing infection. Pooled STD AIDS. 1995;6:305-312. data of 3 Scandinavian studies indicate a 2. Burkman RT, Atienza MF, King TM. relative risk of2.7% (95% CI, 1.4-5.3) of Culture and treatment results in endome- postabortal infection in association tritis following elective abortion. Am J with BV.28 On the basis of randomized- Obstet Gynecol. 1977;128:556-559. 3. Lawton BA, Rose SB, Bromhead C, et al. placebo controlled trials, there is benefit High prevalence of Mycoplasma genita- to perioperative treatment of BV (oral or Hum in women presenting for terminat- rectal metronidazole, vaginal clindamy- ion of pregnancy. Contraception. 2008;77: cin) before surgical abortion compared 294-298. with placebo.28 However, no benefit has 4. Fischer M, Bhatnagar J, Guarner J, et al. been seen in trials that combined treat- Fatal toxic shock syndrome associated ment for BV with 7 days of perioperative with Clostridium sordellii after medical oral doxycycline compared with prophy- abortion. NEJM. 2005;353:2352-2360. laxis with doxycycline alone.28 On the 5. Cohen AL, Bhatnagar J, Reagan S, et al. basis of these findings, it is unclear Toxic shock associated with Clostridum sordeIIii and Clostridium perfringens whether preoperative screening and treat- after medical and spontaneous abortion. ment for BV provides any additional ben- Obstet Gynecol. 2007;110:1027-1033. efit if standard preoperative prophylaxis 6. Stubblefield PG, Grimes OA. Septic is given. abortion. NEJM. 1994;331:310-314. Antibiotic prophylaxis in the setting of 7. Fauveau V, Mamdani M, Steinglass R, incomplete abortion requires further et al. Maternal tetanus: Magnitude, epi- study. A randomized controlled trial of demiology and potential control mea- antibiotic prophylaxis in women with in- sures. Int J Gynecol Obstet. 1993;40:3-12. complete abortion undergoing suction 8. Shannon C, Brothers LP, Philip NM, curettage showed no difference in post- et al. Infection after medical abortion: a abortal fever between groups, however, review of the literature. Contraception. loss to follow-up in this study was 31 %.29 2004;70: 183-190. 9. Westphal JM, Sophocles A, Burggraf H, et aI. Manual vacuum aspiration for first- trimester abortion. Arch Fam Med. 1998; Sunlmal~Y 7:559-562. In the setting of legalized accessible abor- 10. Sutkin G, Capelle SO, Schlievert PM, tion services, risk of postabortion infec- et al. Toxic shock syndrome after lami- tion is low. However, women who present naria insertion. Obstet Gynecol. 2001;98: with signs or symptoms of infection after 959-961.

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11. Evaldson GR, Fianu S, Jonasson A, et al. 21. Durfee SM, Frates MC, Luong A, Does the hygroscopic property of the et al. The sonographic and color doppler laminaria tent imply a risk for ascending features of retained products of conception. infection in legal abortions? A microbio- J Ultrasound Med. 2005;24:1181-1186. logical study. Acta Obstet Gynecol Scand. 22. Kido A, Togashi K, Koyama T, et al. 1986;65:257-261. Retained products of conception mas. 12. Grimes DA. Risks of mifepristone abortion querading at acquired arteriovenous in context. Contraception. 2005;71:161. malformation. J Comput Assist Tomogr. 13. Ashok PW, Templeton A, Wagaarachchi 2003;27:88-92. . PT, et al. Midtrimester medical termina- 23. Acharya G, Morgan H, Paramanantham tion of pregnancy: a review of 1002 con- L, et al. A randomized controlled trial secutive cases. Contraception. 2004;69: comparing surgical termination of preg- 51-58. nancy with and without continuous ultra- 14. Trinder J, Brocklehurst P, Porter R, et al. sound guidance. Eur J Obstet Gynecol Management of miscarriage: expectant, Reprod BioI. 2004;114:69-74. medical, or surgical? Results of random- 24. Debby A, Malinger G, Harow E, et al. ized controlled trial (miscarriage treatment Transvaginal ultrasound after first- (MIST) trial). BMJ. 2006;332:1235-1240. trimester uterine evacuation reduced the 15. Ho PC, Blumenthal PD, Gemzell- indicence of retainded products of con- Danielsson K, et al. Misoprostol for the ception. Ultrasound Obstet Gynecol. 2006; termination of pregnancy with a live fetus 27:61-64. at 13 to 26 weeks. Int J Gynecol Obstet. 25. ACOG Committee on Practice Bulletins. 2007;99:S178-S 181. ACOG Practice Bulletin No. 74. Anti. 16. Pastuszak AL, Schuler L, Speck.Martins .biotic prophylaxis for gynecologic proce- CE, et al. Use of misoprostol during preg- dures. Obstet Gynecol. 2006;I08:225-234. nancy and Mobius' syndrome in infants. 26. Sawaya GF, Grady D, Kelikowske K, N Engl J Med. 1998;338:1881-1885. et al. Antibiotics at the time of induced 17. Nanda K, Peloggia A, Grimes D, et al. abortion: the case for universal prophy- Expectant versus surgical treatment for laxis based on a meta-analysis. Obstet miscarriage. Cochrane Database of Syste- Gynecol. 1996;87:884-890. matic Reviews 2006:Art. No.: CD003518. 27. Caruso S, Di Mari L, Cacciatore A, et al. DOl: 10.1002/14651858.CD003518.pub2. Antibiotic prophylaxis wth prulifloxacin 18. Wen J, Cai QY, Deng F, et al. Manual in women undergoing induced abortion: versus electric vacuum aspiration for a randomized controlled tria. Minerva first-trimester abortion: a systematic re- Ginecol.2008;60:1-5. view. BJOG. 2008;115:5-13. 28. Larsson PG, Bergstrom M, Forsum U, 19. Wong SF, Lam MH, Ho LC. Transvagi- et al. Bacterial vaginosis: transmission, nal sonography in. the detection of role in genital tract infection and preg- retained products of conception after nancy outcome: an enigma. APMIS. first-trimester spontaneous abortion. 2005;113:233-245. J Clin Ultrasound. 2002;30:428-432. 29. Prieto JA, Eriksen NL, Blanco JD. 20. Brown DL. Pelvic ultrasound in the A randomized trial of prophylactic dox- postabortion and postpartum patient. ycycline for curettage in incomplete abor- Ultrasound Q. 2005;21:27-37. tion. Obstet Gynecol. 1995;85:692-696.

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Contraception

,ELSEVIER Contraception 70 (2004) 183-190 Review article Infection after medical abortion: a review of the literature

Caitlin Shannon, L. Perry Brothers, Neena M. Philip, Beverly Winikoff*

Gynuity Health Projects, 15 East 26th Street. Suite 1609. New York. NY /00/0, USA

Received 4 April 2004; received in revised form 30 April 2004; accepted 30 April 2004

Abstract Medical abortion regimens have become widely used, but the frequency of infection after medical abortion is not well documented, This systematic review provides data on infectious complications after medical abortion. We searched Medline for articles written before July 2003 to determine the frequency of infection after medical abortion up to 26 weeks of gestation. We reviewed all articles and extracted data on the frequency of infection from 65 studies. The frequency of diagnosed and/or treated infection after medical abortion was very low (0.92%, N = 46,421) and varied among regimens. Results of this review confirm that, with respect to infectious complications, medical abortion is a safe and effective option for first- and second-trimester pregnancy termination. After accounting for regional variations in diagnosis, there is little difference in frequency of infection among the regimens reviewed. Future studies should report clear diagnosis and treatment standards for infection so that more precise information becomes available. @ 2004 Elsevier Inc. All rights reserved.

Keywords: Medical abortion; Infection; Mifepristone; Misoprostol; Antibiotics

1. Introduction occur 6.0-7.4% of the time after cesarean sections and 5.5% after vaginal deliveries [4], and pelvic infections are Over the past decade, medical abortion regimens have the most common complication of surgical abortion proce- become more widely used to terminate first- and second- dures, with frequencies varying from 0.1% to 4.7% world- trimester pregnancies. From November 2000 to May 2002, wide [5]. Risk of developing infection is a particular con- an estimated 80,000 women received mifepristone for med- cern for providers, because they are keen to avoid serious ical abortion in the United States [I] and over 15 million complications that may jeopardize the health and future medical abortions were performed in China from 1992 to fertility of the predominately young and healthy women 2002 [2]. Regimens using mifepristone accounted for ap- they treat. proximately half of the first-trimester abortions performed Because medical abortion is a noninvasive procedure, in France, Scotland and Sweden, and 18% of the first- there is an expectation that infection after medical abortion trimester abortions in England and Wales from 1990 to could be less frequent than after surgical abortion. Indeed, 2000 [3]. These methods offer' women safe,' effective and data from both Hausknecht [I] and Planned Parenthood acceptable alternatives to surgical procedures. It is impor- (Mary Fjerstad, Planned Parenthood Federation of America, tant, however, to understand the frequency of complications personal communication) suggest the frequency of infec- after medical abortion and to develop proper management tious complications after mifepristone medical abortion is and treatment guidelines in order to provide high-quality very low (considerably less than 1%). Based on US Food care for patients seeking treatment. and Drug Administration (FDA) adverse event reports re- Infections requiring oral or intravenous antibiotic treat- lated to the use of mifepristone (Mifeprex@), a 2003 review ment and/or hospitalization sometimes occur after surgical by Hausknecht found reports from 10 (out of an estimated abortion, childbirth and invasive procedures involving the 80,000) women (0.013%) in the United States who under- female genital tract. Postpartum infection is estimated to went medical abortion treatment with mifepristone who were treated with antibiotics for infections, one of which was serious [1,6]. A review of clinic-based data from the * Corresponding author. Tel.: + 1-212-448-1230; fax: + 1-212-448- Planned Parenthood Federation of America found that 13 1260. E-mail address: [email protected] (8. Winikoft). cases of endometritis requiring intravenous antibiotics and

00 I0- 7824/04/$ - see front matter (Q 2004 Elsevier Inc. All rights reserved. doi: I0.1016/j.contraception.2004.04.009 Case: 3:13-cv-00465-wmc Document #: 245-9 Filed: 06/11/14 Page 2 of 8

184 C. Shannon et al. / Contraception 70 (2004) 183-190 hospitalization were diagnosed among the 58,950 women Therefore, we included cases with confirmed diagnosis of receiving mifepristone medical abortion between January 1, infection and/or those treated with antibiotics for any rea- 2001, and June 30, 2003 (0.022%) (Mary Fjerstad, Planned son, including for "presumptive" infection diagnosed based Parenthood Federation of America, personal communica- on the presence of prolonged bleeding, abdominal pain, tion). offensive discharge and/or pyrexia. Nonetheless, it is not possible to make accurate estimates about rates of infection after medical abortion from these data, because of two key but distinct issues. First, data based 3. Results on regulatory reports are generally presumed to underesti- mate the true incidence of an event, as reporting is voluntary Overall frequency of diagnosed and/or treated infection and unsolicited. Second, data from Planned Parenthood rep- reported after medical abortion treatment was < 1% (0.92%, resent only one clinic system, and thus it is not possible to N = 46,421). Infections were reported after treatment, with generalize from those results to the population of all med- a range of 0.00% to 6.11 % among studies. The most com- ical abortion providers in the United States. The purpose of mon type of postabortal infection reported was endometritis this review is to provide more systematic data on infectious (49%,210/429), followed by undefined "genital tract infec- complications after the five most common medical abortion tion" (37%, 159/429). Both types of infections were usually regimens. diagnosed with no confirmatory tests and treated with no sequelae. In over 46,400 patients receiving medical abortion treatment in these research studies, there was one report of 2. Materials and methods death related to a rare case of Clostridium sordellii sepsis (0.002%) (unpublished data, 2001). There were four cases In order to analyze the frequency of infection after med- (0.009%) of infection requiring hospitalization, of which ical abortion for early pregnancy termination, we searched two were reported after treatment with mifepristone and the Medline database for articles written in English before vaginal misoprostol regimens, one after treatment with July 2003 with the following indexing terms: medical abor- methotrexate and vaginal misoprostol, and one after treat- tion, mifepristone, misoprostol, methotrexate, abortion and ment with mifepristone and oral misoprostol. pregnancy termination. Infection was reported most frequently among women We used the following selection criteria for study inclu~ who received mifepristone followed by gemeprost (Table 1; sion: (a) sample size greater than 100 (although for random- 1.56%, n = 11,501). Of these cases, most (84%, n = ized trials, the sample size for a particular study arm could 11,501) were "presumptive" infections treated with antibi- be less than 100), and (b) the. inclusion of reports on the otics without confirmed diagnosis. Frequency of infection frequency of infection following the medical abortion pro- after treatment with mifepristone and vaginal misoprostol cedure by specific treatment regimen. Articles selected in- (Table 1) was 1.33% (n = 15,292). The most common cluded reports of prospective, retrospective and randomized diagnosis among these women was "presumed genital tract studies. The population for all studies was women who infection" (77.5%, n = 204) based on clinical symptoms of received medical abortion treatment for pregnancy termina- continued pain, vaginal bleeding or offensive discharge, and tion in the first or second trimester. Frequency of infection all were treated with oral antibiotics. Another 15.2% of the was the outcome of interest for our review. We were careful infections were diagnosed as endometritis, and 3.4% were to exclude studies reporting on data that overlapped with diagnosed based on the presence of fever. Six cases were other studies. Using this methodology, we retrieved 85 treated with antibiotics, although no details of diagnosis prospective studies and randomized clinical trials, 74% of were reported. One woman who also underwent laparos- which met the inclusion criteria for our review [7-69]. We copy for suspected ectopic pregnancy recovered fully from also included data from two studies being prepared for a pelvic infection. As described above, one death was re- publication (unpublished data from a study testing a mife- ported as a case of Clostridium sordellii sepsis. pristone and three different misoprostol regimens in Can- The frequency of infection among women treated with ada, 2001; unpublished data from a study testing a mife- mifepristone and oral misoprostol regimens (Table 1; pristone and oral misoprostol regimen in United States, 0.21 %, n = 13,497) was much lower. The vast majority 2002). The review encompassed studies of regimens using (79%, n = 29) of cases were diagnosed as endometritis. Of mifepristone and gemeprost, mifepristone and oral miso- the remaining cases, three were described as infections prostol, mifepristone and vaginal misoprostol, methotrexate requiring only oral antibiotic treatment, one case was treated and vaginal misoprostol, and vaginal misoprostol only, in- with intravenous antibiotics and hospitalization, one case cluding a total of 46,421 women undergoing medical abor- was described as vaginitis and one diagnosis was unspeci- tion procedures. Almost 95% of these women received fied. No other comments were reported on diagnosis, treat- medical abortion treatment before 12 weeks of gestation ment or outcome for these remaining cases. (94.5%, N = 46,421). Among the 3893 women treated with methotrexate and Few studies provided a rigorous definition of infection. vaginal misoprostol regimens (Table 1),6 cases (0.15%) of Case: 3:13-cv-00465-wmc Document #: 245-9 Filed: 06/11/14 Page 3 of 8

C. Shannon et al. / Contraception 70 (2004) 183-190 185

Table I Infection after medical abortion

Author Year Regimen n GA" (wks) % Infection (n)

Regimen: Mifepristone (MP) and gemeprost (GP) b Silvestre et al. [53] 1990 600 mg MP; I mg GP 2115 7 0.09 (2 ) WHO Task Force [68] 1991 25 mg MP or 600 mg MP; I mg GP 385 7 3.64(W) d WHO Task Force [67] 1993 200, 400 or 600 mg MP; I mg GP 1151 8 1.39 (16 ) UK Multicenter Study Group [59] 1997 600 mg MP; I mg GP, up to 5 doses 267 12 0.00 (0) Urquhart et al. [60] 1997 600 mg MP; I mg GP 1018 9 0.00 (0) Bartley et al. [13] 2000 200 mg MP, 0.5 mg GP 2839 9 4.30 (122e) Gemzell-Danielsson, Ostlund [32] 2000 600 mg MP; I mg GP, up to 5 doses 197 14-26 0.00 (0) f Bartley et al. [12] 2001 200 mg MP; 0.5 mg GP 453 9 5.74 (26 ) Tang et al. [58] 2001 200 mg MP; I mg GP, up to 4 doses 956 12-24 0.00 (0) WHO Task Force [65] 2001 200 or 600 mg MP; I mg GP 896 8-9 0.00 (0) WHO Task Force [64] 2001 50 or 200 mg MP; 5 or I mg GP 1224 8 0.00 (0) Total 11,501 1.56 (180)

Regimen: Mifepristone (MP) and vaginal misoprostol (MS) EI-Refaey el al. [30] 1995 600 mg MP; 800 ILg MS 133 9 0.00 (0) g Penney el al. [45] 1995 200 mg MP; 800 ILg MS 360 9 6.11 (22 ) Ho et al. [37] 1997 200 mg MP; 200 ILg MS, up to 5 doses 49 14-20 0.00 (0) Schaff et al. [52] 1997 600 mg MP; 800 ILg MS 168 8 1.79 (3h) Ashok et al. [8] 1998 200 mg MP; 800 ILg MS 2000 9 3.05 (61i) Gouk el al. [33] 1999 200 mg MP; 800 ILg MS 313 9-12 0.32 (Ii) k Schaff et al. [51] 1999 200 mg MP; 800 ILg MS 933 8 0.21 (2 ) Aubeny, Chatellier [9] 2000 600 mg MP; 400 ILg MS 118 7 0.00 (0) . Ngai el al. [43] 2000 200 mg MP; 400 ILg MS, up to 5 doses 71 14-20 0.00 (0) Schaff et al. [50] 2000 200 mg MP; 800 ILg MS 2295 8 0.09 (2') m Schaff et al. [49] 2000 200 mg MP; 800 ILg MS 1137 9 0.35 (4 ) Bartley et al. [12] 2001 200 mg MP; 800 ILg MS 457 9 5.47 (25") Bjorge el al. [14] 2001 600 mg MP; 800 ILg MS 226 9 0.44 (l") Child et al. [24] 2001 200 mg MP; 800 ILg MS 533 9 0.00 (0) Knudsen [41] 2001 600 mg MP; 400 p..gMS 100 8 2.00 (2P) Population Council study-Canadagg 2001 200 mg MP; 800 ILg MS 318 8 0.63 (2q) Schaff et al. [48] 2001 200 mg MP; 800 ILg MS 596 9 0.00 (0) Ashok et al. [7] 2002 200 mg MP; 800 ILg MS 4132 9 1.80 (76') Schaff et al. [47] 2002 200 mg MP; 800 ILg MS 522 9 0.19(1') Tang el al. [57] 2002 200 mg MP; 400 ILg MS 100 9 0.00 (0) Tang et al. [55] 2002 200 mg MP; 800 ILg MS 100 9 0.00 (0) Creinin et al. [26] 2003 200 mg MP; 800 p..g MS 148 9 0.00 (0) Hamoda et al. [35] 2003 200 mg MP; 800 ILg MS 483 7-13 0.41 (2') Total 15,292 1.33 (204)

Regimen: Mifepristone (MP) and oral misoprostol (MS) Aubeny et al. [10] 1991 600 mg MP; 400 p..g MS 1208 7 0.08 (I") McKinley el al. [42] 1993 200 or 600 mg MP; 600 ILg MS 220 9 0.00 (0) Peyron et al. [46] 1993 600 mg MP; 400 ILg MS 505 7 0.00 (0) Peyron et al. [46] 1993 600 mg MP; 400 ILg MS, 200 ILg MS 390 7 0.00 (0) Guo-wei el al. [34] 1994 200 mg MP; 600 ILg MS 149 7 0.00 (0) Guo-wei et al. [34] 1994 50 mg MP, 25 mg MP; 600 ILg MS 301 7 0.00 (0) Aubeny et al. [11] 1995 600 mg MP; 400 ILg MS 1108 7 0.27 (3") EI-Rafaey et al. [30] 1995 600 mg MP; 800 ILg MS 130 9 0.00 (0) Ho et al. [37] 1997 200 mg MP; 200 ILg MS, up to 5 doses 49 14-20 0.00 (0) Winikoff el al. [62] 1997 600 mg MP; 400 p..g MS 1373 8 0.07 (lj X Spitz et al. [54] 1998 600 mg MP; 400 ILg MS 2121 8 0.90 (19 ) Jain et al. [40] 1999 600 mg MP; 400 ILg MS 100 8 1.00 (JY) Ngoc el al. [44] 1999 600 mg MP; 400 ILg MS 257 8 0.00 (0) Aubeny, E Chalellier [9] 2000 600 mg MP; 400 p..g MS 119 7 0.00 (0) ICMR Task Force [38] 2000 200 mg MP; 600 ILg MS 440 4 0.00 (0) Ngai SW et al. [43] 2000 200 mg MP; 400 p..gMS, up to 5 doses 71 14-20 0.00 (0) WHO Task Force [66] 2000 200 or 600 mg MP; 400 ILg MS 1589 5 0.00 (0) Elul et al. [31] 2001 200 mg MP; 400 ILg MS 315 8 0.00 (0) Z Population Council study-Canadagg 2001 200 mg MP; 400 p..g MS 319 8 0.94 (3 ) Population Council study-Canadagg 2001 200 mg MP; 600 ILg MS 319 8 0.00 (0) Schaff et al. [48] 2001 200 mg MP; 400 ILg MS, 2 doses 548 9 0.00 (0) (Continued) Case: 3:13-cv-00465-wmc Document #: 245-9 Filed: 06/11/14 Page 4 of 8

186 C. Shannon et 01./ Contraception 70 (2004) 183-190

Table I continued

Author Year Regimen n GA" (wks) % Infection (n)

Coyaji et al. [25] 2002 600 mg MP; 400 /Lg MS 874 9 0.00 (0) g 0.28 (I"') Population Council study-US " 2002 200 mg MP; 400 /Lg MS 353 7 Schaff et al. [47] 2002 200 mg MP; 400 /Lg MS, 800 /Lg MS 489 9 0.00 (0) Tang et al. [55] 2002 200 mg MP; 800 /Lg MS 50 9 0.00 (0) Tang et al. [57] 2002 200 mg MP; 800 /Lg MS 100 9 0.00 (0) Total 13,497 0.18 (29)

Regimen: methotrexate (MT) and vaginal misoprostol (MS) Hausknecht [36] 1995 50 mg 1M MT; 800 /Lg MS 178 9 0.00 (0) Creinin et al. [29] 1996 50 mg 1M MT; 800 /Lg MS 300 7 0.00 (0) Carbonell-Esteve et al. [23] 1997 50 mg 1M MT; 800 /Lg MS 287 9 0.35 (I bb) Creinin et al. [28] 1997 50 mg oral MT; 800 /Lg MS 300 7 0.00 (0) Wiebe [61] 1997 50 mg 1M MT; 750 or 500 /Lg MS 289 7 0.00 (0) Carbonell et al. [21] 1998 50 mg oral MT; 800 /Lg MS 300 9 1.00 we) Creinin et al. [27] 1999 50 mg 1M MT; 800 /Lg MS 240 7 0.00 (0) dd Borgatta et aI. [15] 200 I 50 mg 1M MT; 800 /Lg MS 1973 7 0.10 (2 ) Creinin et al. [26] 2003 50 mg 1M MT; 800 /Lg MS 26 9 0.00 (0) Total 3893 0.15 (6)

Regimen: vaginal misoprostol (MS) only Bugalho et al. [18] 1993 800 /Lg MS; 800 /Lg MS 169 12-23 0.00 (0) Bugalho et al. [17] 1996 200 or 400 /Lg MS, up to 4 doses 134 II 0.00 (0) Carbonell et al. [22] 1997 800 /Lg MS (moistened with water), up to 3 doses 141 10 0.00 (0) Wiebe [61] 1997 600 /Lg MS, 3 doses 241 7 0.00 (0) Wong et al. [63] 1998 400 /Lg MS, up to 5 doses 70 14-20 0.00 (0) ee Carbonell et al. [20] 1999 800 /Lg MS (moistened with water), up to 4 doses 720 9 1.25 (9 ) Jain et al. [40] 1999 800 /Lg MS, 800 /Lg MS 100 8 1.00 (lIT) Bugalho et al. [16] 2000 800 /Lg MS 103 6 0.00 (0) Carbonell et al. [19] 2001 1000 /Lg MS, up to 3 doses 300 7 0.00 (0) Jain et al. [39] 2001 800 JJ.gMS, up to 3 doses 100 8 0.00 (0) Zikopoulos et al. [69] 2002 800 /Lg MS, up to 3 doses 160 8 0.00 (0) Total 2238 0.45 (10)

Grand total 46,421 0.92 (429)

" Gestational age based on Ist day of last menstrual period.

b Case I: Endometritis; Case 2: Salpingitis; no comments given on care or outcome. e Antibiotic therapy given to prevent or cure suspected genitourinary infection.

d Antibiotics given for suspected pelvic or upper genital tract infections.

C Diagnosed with presumed endometritis by clinical symptoms.

f Given antibiotics for clinically diagnosed endometritis. g 20 women given antibiotics for prolonged bleeding or offensive discharge; 2 women with pyrexial illness given IV antibiotics, I to 3 days after medical abortion.

h Endometritis; no details on treatment i Given antibiotics for presumed genital tract infection (symptoms: continued pain, vaginal bleeding, offensive discharge). j Pyrexia treated with antibiotics.

k Mild endometritis, given oral antibiotics.

I Antibiotics.

m Antibiotics.

n Given antibiotics for clinically diagnosed endometritis. o One woman required surgical intervention due to abdominal pain and suspected infection; treated with antibiotics.

p 2 patients with "pyrexia, pain, discharge" given antibiotics and evacuation.

q One report of death related to a rare case of Clostridium sordelli sepsis; one case treated with oral antibiotics. r 66 women with presumed genital tract infection based on symptoms (continued pain, vaginal bleeding, offensive discharge) treated with antibiotics; 10 women had unscheduled visits to hospital and were treated with antibiotics for presumed infection.

S Endometritis treated with oral antibiotics.

I Pyrexia (Temperature >38°C).

n Vaginitis.

v Endometritis.

W Unspecified; visited another hospital for "infection". x Endometritis with one severe case.

Y Endometritis.

Z Infections treated with oral antibiotics. ". Treated with IV antibiotics and hospitalization. bb I presumptive septic endometritis with remains; no comments on treatment.

co 3 presumptive septic endometritis with remains; given antibiotics.

dd Two women had postabortal infections, one requiring hospitalization.

co Given antibiotics. ITEndometritis.

gg Population Council, unpublished data. Case: 3:13-cv-00465-wmc Document #: 245-9 Filed: 06/11/14 Page 5 of 8

C. Shannon et al. / Contraception 70 (2004) 183-190 187

Table 2 Aggregate frequencies

Regimen Overall UK studies Non-UK studies

N n % N n % N n %

Mifepristone and vaginal misoprostol 15,292 204 1.33 8471 187 2.21 6,821 17 0.25 Mifepristone and oral misoprostol 13,497 29 0.21 350 0 0.00 13,147 29 0.22 Mifepristone and gemeprost 11,501 180 1.57 4381 148 3.38 7120 32 0.45 Methotrexate and vaginal misoprostol 3893 6 0.15 0 0 0.00 3893 6 0.15 Vaginal misoprostol alone 2238 10 0.45 0 0 0.00 2238 10 0.45 Total 46,421 429 0.92 13,202 335 2.54 33,219 94 0.28

infection were reported. Four cases were diagnosed as pre- Canada and the United States (no patients treated in the sumptive endometritis (three of whom were treated with UK). antibiotics), and two cases were reported without diagnostic Excluding data from the UK studies (n = 13,302), the details. Frequency of reported postabortal infection among overall frequency of infection after all medical abortion women who received regimens of misoprostol (vaginally) regimens decreases from 0.92% to 0.28% (p < 0.0001). only (Table I) was similarly low (0.45%, n = 2238). One Additionally, when the UK data are excluded, there appears case was defined as endometritis, and nine cases were not to be essentially no difference between frequencies of in- described beyond having received antibiotic treatment. fection for the two routes of prostaglandin administration Out of 46,421 women described in these studies, 930 (0.25% after vaginal administration and 0.22% after oral; p women were treated with medical abortion regimens late in = 0.081). Therefore, it is very likely that there is no mean- the first trimester (10-14 weeks gestation). Three of the 930 ingful difference in infection frequency by route of admin- women (0.32%) were treated for infectious complications. istration of misoprostol. There were no infections reported among the 1632 women treated in the second trimester (14-26 weeks gestation). Regional variation in diagnostic criteria and treatment 4. Discussion procedures may affect the reported frequency of infection after medical abortion procedures. When data were ana- As this review of studies examining five types of medical lyzed according to region, frequency of infection in the UK abortion regimens clearly demonstrates, overall frequency studies was higher than that in studies carried out elsewhere of reported infection after medical abortion procedures (Table 2). For example, frequency of postabortal infection (0.92%) is lower than that reported after either surgical in women who received mifepristone and vaginal misopros- abortion procedures or childbirth. The rate of women lost to tol in the United Kingdom is almost 10 times higher than follow-up was quite low «5%) in most of the studies we that reported among women receiving the same method of reviewed. Therefore, it is unlikely that loss to follow-up treatment outside of the UK (2.21%, n =8471 and 0.25%, affected the reported frequency of infection. Several other n = 6821, respectively; p < 0.0001). Further, although methodological issues, however, do limit the analysis of studies from the United Kingdom make up only 55% of the infection after medical abortion in this review. Most impor- data on regimens using mifepristone and vaginal misopros- tant, many different definitions and diagnostic standards for tol, they account for 92% of the infections reported after infection were used in the studies evaluated. treatment with this regimen. Reports of infection in the large Treatment with any type of postprocedural antibiotic series of mifepristone and gemeprost studies performed in (oral or intravenous) most commonly served as a proxy for the United Kingdom manifest the same pattern: standard diagnosis of infection. Antibiotics were often given for treatment for "presumptive" infections and a higher than "presumptive" diagnoses based on one or more of the after average reported frequency of infection (3.38%, n = 4381 symptoms: prolonged bleeding, abdominal pain, offensive in UK studies as compared to 0.45%, n = 7120 in non-UK discharge and pyrexia, especially in certain medical cul- studies; p < 0.0001) tures. While treatment of presumptive infection may be an In contrast, reported frequency ofpostabortal infection in appropriate standard of care, using such treatment as a studies both of methotrexate and vaginal misoprostol and of proxy for infection likely results in an overestimate of the mifepristone and oral misoprostol are lower than the overall true frequency of infection. Furthermore, some of the re- average (0.15% and 0.21 %, respectively, as compared to the corded use of antibiotics could derive from prophylactic overall frequency of 0.92%, p < 0.0001 for both differ- antibiotics before surgical completion of failed medical ences). Studies including oral misoprostol administration abortions, adding to the overestimate of the true frequency were carried out predominantly in France and the United of infection after medical abortion. States (only 2.6% of such patients were treated in the UK), Regional differences in the reported frequency of infec- and methotrexate studies were carried out predominantly in tion may be evidence that the diagnosis and treatment of Case: 3:13-cv-00465-wmc Document #: 245-9 Filed: 06/11/14 Page 6 of 8

188 C. Shannon et al. / Contraception 70 (2004) /83-/90 infection depends heavily on medical practice and physician and safer and more effective treatment regimens can be behavior. This inconsistency limits our ability to calculate a established. Results of this review confirm that, with regard true frequency of infection after medical abortion. There is to infectious complications, medical abortion treatments some evidence that regional variation in clinical practice appear to be safe and effective options for terminating early may impact reported frequency of infection, as the overall pregnancies. frequency of infection (0.92%) is much lower than the frequency reported in the UK studies (2.54%). Indeed, overall frequency of infection may be elevated Acknowledgments because antibiotic treatment is standard practice for "pre- sumptive" infection signaled only by prolonged bleeding or The authors wish to thank Mary Fjerstad of the Planned pain in the United Kingdom. In comparison, in France, the Parenthood Federation of America for her contribution of United States and Canada, treatment of presumptive infec- clinic data. We thank the Packard Foundation for their tions is not commonly reported. This difference- between support. treatment of infection in the United Kingdom and other regions-is one possible explanation for the lower fre- quency of infection for the two regimens tested predomi- References nantly outside of the United Kingdom, mifepristone and oral misoprostol and methotraxate and vaginal misoprostol. (I] Hausknecht R. Mifepristone and misoprostol for early medical abor- In fact, when studies from the United Kingdom were ex- tion: 18 months experience in the United States. Contraception 2003; cluded, there were no significant differences in frequency of 67:463-5. infection among the regimens. Therefore, the relatively [2] Zhou, R, Elul B, Winikoff B. 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Serdar E. Bulun, MD

Personal: Citizenship: U.S. Marital Status: Married to Lina Bulun; has one son, Erol Bulun Home address: 1016 West Montana, Chicago, IL 60614

Current Position: 3/2012 - Present John J. Sciarra Professor and Chair Department of Obstetrics and Gynecology Northwestern University Feinberg School of Medicine 250 East Superior Street, Suite 03-2306 Chicago, Illinois 60611 Tel: (312) 472-3636 Fax: (312) 472-3740 Email: [email protected]

Past Academic Appointments: 2003 - 2012 Professor (with tenure) George H. Gardner, MD, Professor of Clinical Gynecology Chief, Division of Reproductive Biology Research Department of Obstetrics and Gynecology Northwestern University of Feinberg School of Medicine

1999 - 2003 Associate Professor (with tenure) of Obstetrics and Gynecology and Molecular Genetics Director, Division of Reproductive Endocrinology and Infertility University of Illinois at Chicago

1993 - 1999 Assistant Professor of Obstetrics and Gynecology Green Center for Reproductive Biology Sciences University of Texas Southwestern Medical Center at Dallas

1997 - 1999 Associate Director, Reproductive Endocrinology Fellowship Program Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center at Dallas

Education: 1991 - 1993 Subspecialty Fellowship (Reproductive Endocrinology and Infertility) University of Texas Southwestern Medical Center at Dallas

1988 - 1991 Residency: Obstetrics and Gynecology State University of New York at Buffalo

1987 - 1988 Internship: Obstetrics and Gynecology, Harlem Hospital Columbia University College of Physicians and Surgeons, New York

1986 - 1987 Residency: Pathology, University of Arizona College of Medicine, Tucson, AZ

1983 - 1986 Family Practitioner, Gazipasa Hospital, Antalya, Turkey

1977 - 1983 Doctor of Medicine, Istanbul University School of Medicine, Istanbul, Turkey

1 Exh. 500 Case: 3:13-cv-00465-wmc Document CURRICULUM #: 245-10 VITAE Filed: 06/11/14 Page 2 of 31

Serdar E. Bulun, MD

1973 - 1977 American Robert College (Preparatory High School), Istanbul, Turkey

Board Certifications and Medical Licensure:  Board certified in Reproductive Endocrinology and Infertility, 1996  Board certified in Obstetrics and Gynecology, 1994  Illinois Medical License, #036-099872; Texas License #J0448; New York License, #180408

Hospital Staff Appointments:  Northwestern Memorial Hospital, Chicago, IL (Staff physician, 7/1/2003-present)  University of Illinois at Chicago Medical Center (Staff physician, 2/22/1999-6/30/2003)  Parkland Memorial Hospital, Dallas, TX (Staff physician, 8/1/1991-2/21/1999)  St. Paul Hospital, Dallas, TX (Staff physician, 8/1/1993-2/21/1999)  Zale-Lipshy University Hospital, Dallas, TX (Staff physician, 8/1/1993-2/21/1999)

Honors, Professional and Scientific Service: Endowed Appointments:  John J. Sciarra Professor, Northwestern University, 2012 – present  George H. Gardner, MD, Professor of Clinical Gynecology, Northwestern University, 2006-2012  Friends of Prentice Distinguished Physician in Obstetrics and Gynecology, Northwestern Memorial Hospital, 2003-2007

Honor Societies:  Association of American Physicians (AAP, elected 2012)  American Gynecological and Obstetrical Society (AGOS, elected 2007)  American Society for Clinical Investigation (ASCI, elected 2003)

National Leadership Positions, Societies And Boards:  President-elect, Society for Gynecologic Investigation (SGI, ~1,000 members, 2015)  Council, Society for Gynecologic Investigation (elected, 2009-2012)  Program Chair, Annual Meeting, American Society for Reproductive Medicine (ASRM, ~7,000 members, Boston 2013)  Program Chair, Annual Meeting, Society for Gynecologic Investigation, Los Angeles, CA, 2002

Awards:  American Society for Reproductive Medicine (ASRM) Distinguished Researcher (Star) Award, 2012  NIH-MERIT Award 2010  University of Illinois at Chicago – University Scholar Award, 2002  Society for Gynecologic Investigation President’s Achievement Award, 2002  Charles E. Hunter, Jr. Prize Thesis Award, AAOGF, 1999  Society for Gynecologic Investigation Meeting, President’s Prize, 1999  American Society for Reproductive Medicine Meeting, SRE Prize Paper Award, 1998  American Society for Reproductive Medicine Meeting, SRE Prize Paper Award, 1996  AAOGF – Walter Dannreuther Fellowship Award, 1994-96  Society for Gynecologic Investigation Meeting, President’s Prize, 1995  Society for Gynecologic Investigation – Mead Johnson Research Award, 1993  American Fertility Society Meeting, SRE Prize Paper Award, 1992

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 Marcos Gallego Award by S.U.N.Y. at Buffalo Dept. of Ob/Gyn, 1991  Buffalo Gynecologic and Obstetric Society Award for Clinical Excellence, 1990

Editor:  Associate Editor, Seminars of Reproductive Medicine, 2011-2014  Associate Editor, Journal of Endometriosis, 2012  US Editor, Journal of Molecular Endocrinology, 2008-2012  Editor-in-Chief-elect, Seminars in Reproductive Medicine, 2014

Editorial Boards:  Endocrinology, 2013-2017  Journal of Clinical Endocrinology and Metabolism, 1998-2001; 2005-2008; 2012-2014  Endocrine Reviews, 2008-2011  Seminars in Reproductive Medicine, 2005-2010  Steroids, 2004-2008

Scientific Review Panels: 2001 – 2005 Member, NIH-Integrative and Clinical Endocrinology and Reproduction (ICER) Study Section

1996 - 1999 Member, Endocrinology Review Panel, Department of Defense Breast Cancer Research Program

1999 – Present Ad hoc reviewer for NIH Study Sections: Reproductive Endocrinology (REN) Biochemical Endocrinology (BCE) Molecular and Cellular Endocrinology (MCE) Tumor Micro-Environment (TME) Center for Inherited Disease Research (CIDR) Genomics, Computational Biology and Technology Study Section (GCAT) NCI-P01 site visit teams (breast cancer, uterine fibroids) Specialized Centers of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health Specialized Cooperative Centers Program in Reproduction Research (U54-SCCPRR) Numerous Special Emphasis Panels

Publication Evaluation (Reviewer):  American Journal of Obstetrics and Gynecology  Biology of Reproduction  Cancer Research  Clinical Cancer Research  Endocrine Reviews  Endocrine-Related Cancer  Endocrinology  Fertility and Sterility  Human Reproduction  Human Reproduction Update  Journal of Clinical Endocrinology and Metabolism  Journal of Clinical Investigation

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 Journal of Molecular Endocrinology  Journal of the American Medical Association  Journal of the Society for Gynecologic Investigation  Journal Steroid Biochemistry and Molecular Biology  Lancet  Molecular and Cellular Endocrinology  Molecular Endocrinology  Nature  Nature Communications  Nature Genetics  Nature Medicine  New England Journal of Medicine  Obstetrics and Gynecology  PLoS One  Proceedings of National Academy of Sciences USA  Reproductive Sciences  Science  Science Translational Medicine  Trends in Endocrinology and Metabolism

Philanthropy:  Medical Advisory Committee, Lynn Sage Cancer Research Foundation, Chicago, IL, 2011-present  Member, Board of Directors, Friends of Prentice, Chicago, IL, 2005-present

Organized Scientific Symposia:  Chair, American Society for Reproductive Medicine, Fibroid Post-Graduate Course, 2011  Chair, Society for Gynecologic Investigation Symposium, Washington, DC, 2010  Chair, Endocrine Society Symposium, San Francisco, CA, 2008  Chair, American Society for Reproductive Medicine Endometriosis Post-Graduate Course, San Francisco, CA, 2008  Chair, Society for Gynecologic Investigation Symposium, Reno, NE, 2007  Co-Chair, Advances in Breast Cancer Research, Northwestern University Cancer Center-Sponsored Conference, Chicago, IL, 2007.  Chair, Society for Gynecologic Investigation Symposium, Los Angeles, CA, 2005  Chair, Society for Gynecologic Investigation Symposium, Washington, DC, 2003  Chair, Society for Gynecologic Investigation Postgraduate Course. Innovations in Endometriosis Research, Los Angeles, CA, 2002.  Chair, Society for Gynecologic Investigation Symposium, Toronto, ON, 2001  Chair, Society for Gynecologic Investigation Symposium, Philadelphia, PA, 1996.

Board Examiner:  Oral Subspecialty Boards in Reproductive Endocrinology and Infertility, 2002-present

Invited Expert To:  1st US-Russian Scientific Forum (NIH-Russian Academy of Sciences), Moscow, Russia, 2011  NIH/NICHD VISION Workshop, Leesburg, VA, 2011  NIH/NICHD Workshop on Reproduction, Bethesda, MD, 2011  National Clinical Research Panel sponsored by AMA and AAMC, Chicago, IL, 1998

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 In Vitro Fertilization Program, King Faisal Specialist Hospital, Riyadh, Saudi Arabia, 1995

Invited speaker to selected meetings (out of >180): Plenary Presentations:  Japan Society of Obstetrics and Gynecology Meeting, (JSOG) 66th Annual Conference, Tokyo, 2014 (~5,000 participants)  American Gynecological and Obstetrical Society (AGOS) Meeting, Chicago, IL 2011(~ 300 participants)  American Society for Reproductive Medicine (ASRM) Meeting, Denver, CO, 2010 (~5,000 participants)  Canadian Fertility and Andrology Society Meeting, Vancouver, BC, 2010 (~1,000 participants)  Japanese Society for Reproductive Medicine (JSRM) Meeting, Kanazawa, Japan, 2009 (~2,000 participants)  International Congress (8th) of the Turkish-German Gynecological Education and Research Foundation, 2009 (~2,000 participants)  Japan Society of Obstetrics and Gynecology (JSOG) 60th Annual Conference, 2008 (~5,000 participants)  European Society for Pediatric Endocrinology (ESPE), Istanbul, Turkey, 2008 (~3,000 participants)  International Congress (2nd) on Reproductive Medicine: Family Reproductive Health at the Russian Academy of Sciences, Moscow, Russia, 2008 (~2,000 participants)  Turkish Society of Reproductive Medicine Meeting (3rd), Antalya, Turkey, 2008 (~1,500 participants)  Central Association of Obstetrics and Gynecology, San Diego, CA, 2003 (~800 participants)  International Congress (5th) of the Turkish-German Gynecological Education and Foundation, 2003 (~2,000 participants)  Society for Gynecologic Investigation Meeting, Chicago, IL, 2000 (~1000 participants)

Gordon Conferences:  Gordon Research Conference on Reproductive Tract Biology, NH, 2010  Gordon Research Conference on Reproductive Tract Biology, NH, 2004  Gordon Research Conference on Hormonal Carcinogenesis, NH, 2003  Gordon Research Conference on Reproductive Tract Biology, Hartford, CT, 2002

National/ International Meetings:  Society for Gynecologic Investigation International Summit Meeting, Istanbul, Turkey, 2013  NIH-NICHD Subspecialty Fellows Conference, Chicago IL, 2012  Avon Breast Cancer Symposium, , 2011  International Pelvic Pain Society Meeting, Istanbul, Turkey, 2011  Symposium, Society for Gynecologic Investigation, Miami, FL 2011  World Congress (14th) of Gynecological Endocrinology, Florence, Italy 2010  Symposium, Society for Gynecologic Investigation, Washington, DC, 2010  Symposium, American Society for Reproductive Medicine, Atlanta, GA, 2009  Society of Toxicology 48th Annual Meeting & ToxExpo, Baltimore, Maryland, 2009  International Aromatase Conference (10th), Shanghai, China 2008  NIH-NICHD Workshop (3rd) on Uterine Leiomyomata, Bethesda, MD, 2008  Symposium, Endocrine Society, 90th Annual Meeting, San Francisco, CA, 2008  International Adrenal Cortex Conference, San Francisco, CA, 2008  Hormonal Carcinogenesis Conference, Ettore Majorana Centre for Scientific Culture in Erice, Sicily, Italy 2008  Post-Graduate Course, American Society for Reproductive Medicine San Francisco, CA, 2008  Symposium, Society for Gynecologic Investigation, Reno, NV, 2007  The Chinese Medical Association Shanghai Branch OB/GYN Workshop, Shanghai, China 2006  The 20th Meeting of the Research Society of Growth Disturbance in Children (Keynote Speaker), Tokyo, Japan 2006

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 Turkish Society of Reproductive Medicine Meeting (2nd), Antalya, Turkey, 2006  International Aromatase Conference (9th) at the University of Maryland, Baltimore, MD, 2006  Symposium, American Society for Reproductive Medicine, Philadelphia, PA, 2006  International Meeting (3rd) on the Female Reproductive Tract, Frauenchimsee, Germany, 2005  Congress (6th) of the European Society of Gynecology, Helsinki, Finland, 2005  Workshop on 11beta- and 17beta-HSDs, Castle Elmau, Germany, 2005  World Endometriosis Congress (4th) on Endometriosis, Maastricht, Netherlands, 2005  GlaxoSmithKline Nuclear Receptor Conference, Research Triangle Park, NC, 2005  NIH-NICHD Workshop (2nd) on Uterine Leiomyomata, Bethesda, MD, 2005  Symposium, American Society for Reproductive Medicine, Montreal, Quebec, 2005  International Aromatase Conference (8th), Edinburgh, UK, 2004  Turkish Society of Reproductive Medicine Meeting (1st), Istanbul, Turkey, 2004  Symposium, American Society for Reproductive Medicine, San Antonio, TX, 2003  University of Illinois at Urbana Champaign, Symposium on Reproduction, 2003  Southwest Gynecologic Assembly, Dallas, TX, 2003  Symposium, European Society of Human Reproduction and Embryology (ESHRE) Meeting, Madrid, Spain, 2003  Serono International Symposium on Embryo Implantation, Madrid, Spain, 2003  Symposium, Society for Gynecologic Investigation Meeting, Washington, DC, 2003  Research Scientist Development Program Meeting, Scottsdale, AZ, 2002  Symposium, European Society of Human Reproduction and Embryology (ESHRE) Meeting, Vienna, Austria, 2002  International Congress (2nd) on Menopause and Osteoporosis, Istanbul, Turkey, 2002  Serono International Symposium on Embryo Implantation, Uncasville, CT, 2002  World Congress (1st) on Hormonal and Genetic Basis for Sexual Differentiation, Tempe, AZ, 2002  International Aromatase Conference (7th), Kyoto, Japan, 2002  NIH-NCI Workshop on Endometrial Cancer, San Francisco, CA, 2002  Symposium, Society for Gynecologic Investigation Meeting, Los Angeles, CA, 2002  World Congress (3rd) on Endometriosis, San Diego, 2002  French Endocrine Society Meeting, Lyon, France, 2001  Serono International Symposium on Embryo Implantation, Madrid, Spain, 2001  NIH-NICHD Workshop on Endometriosis, Bethesda, MD, 2001  Symposium, Society for Gynecologic Investigation Meeting, Toronto, ON, 2001  International Aromatase Conference (6th), Port Douglas, Australia, 2000  International Conference on Women’s Cancers, Monash University, Melbourne, Australia, 1999  Symposium, Endocrine Society, San Diego, CA, 1999  Ann Scientific Symposium (7th), Prince Henry’s Inst of Med Research, Monash Univ, Melbourne, Australia, 1999  International Congress (3rd) of the Turkish-German Gynecological Education and Foundation, 1999  International Congress (5th) on Aromatase and its Inhibitors, Prague, Czech Republic, 1998  World Congress (16th) on Fertility and Sterility, San Francisco, CA, 1998  World Congress (1st)on Endometriosis, Quebec City, Canada, 1998  Symposium, American Society for Reproductive Medicine, Cincinnati, OH, 1997  International Congress (2nd) of the Turkish-German Gynecological Education and Foundation, 1997  Reinier de Graaf Symposium (9th), Noordwijk, The Netherlands, 1996  Turkish Endocrine Society Meeting (Keynote Speaker), Istanbul, Turkey, 1996  International Aromatase Conference (4th), Lake Tahoe, CA, 1996  Symposium, Society for Gynecologic Investigation Meeting, Philadelphia, PA, 1996  Symposium, Society for Gynecologic Investigation Meeting, Chicago, IL, 1995  International Congress (9th) on Hormonal Steroids, Dallas, TX, 1994

Named Lectureships:  Marsh Poulson, MD Memorial Lecture, University of Utah, Salt Lake City, UT 2011

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 David G. Hall Lecture, University of Missouri, Columbia, MO, 2007  Louis L. Friedman Memorial Lecture in Reproductive Endocrinology, University of Minnesota, 2004

Grand Rounds and Seminars:  Department of Physiology Seminar Series, Southern Illinois University, Carbondale, IL, 2013  Developmental and Regenerative Biology Seminar University of Kansas Medical Center, Kansas City, 2011  Department of Obstetrics and Gynecology Grand Rounds, Xian 4th Military Medical School, Xian, China, 2011  Department of Obstetrics and Gynecology Grand Rounds, University of Michigan,Ann Arbor, MI, 2010  Department of Obstetrics and Gynecology Grand Rounds, University of Florida, Gainesville, FL, 2010  Department of Obstetrics and Gynecology Grand Rounds, Chiba University Medical School, Tokyo, Japan, 2009  Annual Frank R. Lock Symposium (33rd), Obstetrics and Gynecology, Wake Forest University, Winston-Salem, NC, 2009  Department of Cell Biology and Biochemistry Seminars, Texas Tech University, Lubbock, TX, 2009  Veterinary Integrative Biosciences Seminars, Texas A&M University, 2009  Department of Molecular Medicine Grand Rounds, UT San Antonio, TX, 2009  Seminars in Endocrinology at Johns Hopkins School of Medicine, Baltimore, MD, 2009  Reproductive Biology Seminar Series, UT Southwestern Medical Center, 2009  Endocrinology-Reproductive Physiology Program Seminar at the University of Wisconsin-Madison, 2009  Annual Pediatric Endocrinology Symposium, Maimonides Medical Center, Brooklyn, NY, 2009  Department of Physiology Research Seminar Program at Medical College of Georgia School of Medicine, 2008  Department of Obstetrics and Gynecology Grand Rounds at Baylor University College of Medicine, 2008  Reproductive Medicine Speaker Series at Massachusetts General Hospital, Boston, MA, 2007  Cancer Basic Science Seminar at Loyola University Medical Center, Maywood, IL 2007  Department of Obstetrics and Gynecology Grand Rounds at Cornell University, New York, NY 2007  Reproductive Endocrinology and Infertility Lecture Series at Brigham and Women’s Hospital, Boston, MA 2006  Annual Symposium, Department of Obstetrics and Gynecology, Wayne State, Detroit, MI, 2006  Department of Obstetrics and Gynecology Grand Rounds, University of Chicago, Chicago, IL, 2005  St Clara Valley Hospital Obstetrics and Gynecology Grand Rounds, San Jose, CA 2004  Reproductive Biology Seminar Series, UT Southwestern Medical Center, 2003  Department of Obstetrics and Gynecology Grand Rounds, University of Munich, Germany, 2003  Department of Obstetrics and Gynecology Grand Rounds, Tohoku University, Sendai, Japan, 2002  Obstetrics and Gynecology Symposium, University of Chicago, Chicago, IL, 2001  Endocrinology Seminars, University of Chicago, Chicago, IL, 1996  Department of Obstetrics and Gynecology Grand Rounds, University of Chicago, Chicago, IL, 1996  Department of Obstetrics and Gynecology Grand Rounds, University of West Virginia, Charleston, WV, 1994

Committees:  Member, Appointment, Promotion and Tenure Review (APT) Committee, Feinberg School of Medicine, Northwestern University (2009-2012)  Member, Supra-Departmental Committees for Faculty Search in Cancer and Genetics, Northwestern University (2003- 2007)  Chair, Fibroid Special Interest Group, American Society for Reproductive Medicine, 2010-2013  Chair, Continuing Medical Education Committee of the Society for Reproductive Endocrinology and Infertility, ASRM Annual Meeting 2007-2011  Chair, 4 ad hoc APT Committees at Feinberg School of Medicine, Northwestern University (2004-2008)  Member, Dean’s Committee for the “Merger of Department of Molecular Genetics and Department of Biochemistry and Molecular Biology”, UIC College of Medicine (1999-2000)  Member, Search Committee for the Chair of Department of Molecular Genetics and Biochemistry, UIC College of Medicine (2001-2002)

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Society Memberships:  American Society for Biochemistry and Molecular Biology  Society for Gynecologic Investigation  Fellow, American College of Obstetricians and Gynecologists  Endocrine Society  American Society for Reproductive Medicine  Society of Reproductive Endocrinologists  American Medical Association

Teaching: 2005 - Present Didactic Teaching, Reproductive Section (Northwestern University); Scientific Basis of Medicine; second year medical students; lecturer

2005 - 2006 Mentoring the Mentors (Northwestern University); Faculty Affairs Office of the Feinberg School of Medicine

1999 - 2003 Didactic Teaching, Molecular Genetics (University of Illinois at Chicago); Molecular Genetics of Hormone Production; first year medical students; lecturer.

1999 - 2003 Didactic Teaching, Obstetrics-Gynecology (University of Illinois at Chicago); Reproductive Endocrinology and Infertility; third year medical students; lecturer.

1997 - 1999: Associate Fellowship Director of Reproductive Endocrinology Program, Dept. of Obstetrics- Gynecology

1996 - 1999: Didactic Teaching, Obstetrics-Gynecology (UT Southwestern Med School in Dallas); Reproductive Endocrinology and Infertility; third and fourth year medical students; lecturer.

1994 - 1999: In charge of weekly Green Center Clinical Conferences for Reproductive Endocrinology Fellows

Graduate PhD Students:  Diana Monsivais, MS, Integrated Graduate Program, Northwestern (2009-present)  Antonia Navarro, BS, Integrated Graduate Program, Northwestern (2009-present)  Bertan Yilmaz, PhD; Physiology and Biophysics, UIC (2001-2008)

Graduate MD/PhD Students:  Christopher Brooks, BS; Integrated Graduate Program, Northwestern (2007-2012)  Sanober Amin, MD PhD; Molecular Genetics, UIC (2000-2007)

M.D. Students (Research Fellowship):  Jonas Owens, MS-II (2011, Northwestern), “Progesterone Actin in Uterine Leiomyoma”, (Funded by Northwestern University)

 Carrie Richardson, MS-I (2009, Northwestern), “TGF action in Uterine Leiomyoma”, (Funded by Northwestern University)

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 Meghan O’Halloran, MS-II (2007, Northwestern University), “Regulation of ADORA-1 in Breast Cancer”

 Newton Lee, MS-II (2005, Northwestern University), “Regulation of Aromatase Expression and its Inhibition in Breast Cancer”, (Funded by the Robert H. Lurie Comprehensive Cancer Center)

 Karen Maxey, MS-I (2000, Univ. of Chicago Med. School rotating at UIC), “Regulation of Estrogen Metabolism”, (Funded by a Minority Supplement Grant from the NICHD)

 Jeff Smok, MS-III (1995, University of West Virginia rotating at UT Southwestern), “Regulation of Aromatase P450 in Hepatocellular Cancer Cells”

 Joanne Rink, MS-II (1994), UT Southwestern Medical School in Dallas, “Distribution of Fibroblasts and Aromatase P450 Transcripts in Breast Adipose Tissue”, (Presented during the 1995 National Student Research Forum, Galveston, TX)

Residents (for whom Dr. Bulun served as a Research Mentor):  Kara Goldman (2010 - 2012, Northwestern), “Treatment of Endometriosis: Aromatase Inhibitors”

 Irene Moy, MD (2006 - 2008, Northwestern), “Treatment of Endometriosis: Aromatase Inhibitors”

 Elizabeth Barbieri, MD (2004 - 2005, Northwestern), “Aromatase in Endometrium as Diagnostic Marker for Endometriosis”

 Fadi Abu Shahin, MD (2003 - 2004, Northwestern), “Estrogen Metabolism in Endometrium and Implantation”

 S. Fouad, MD (2002 - 2003, UIC), “Ovulation Induction with an Aromatase Inhibitor”

 Radhika Ailawadi, MD (2001 - 2002, UIC), “Treatment of Endometriosis with an Aromatase Inhibitor”

 Meera Kataria, MD (2000 - 2001, UIC), “Treatment of Endometriosis with an Aromatase Inhibitor”

 Michael Ebough, MD (1997 - 1998, UT Southwestern), “Molecular Analysis of Testosterone-Secreting Tumors of Pregnancy”

Postdoctoral Fellows:  Jiajia Ma, MD (2011-present)

 Matthew Dyson, PhD (2010-present)

 Masanori Ono, MD, PhD, (2010-present)

 Toshiyuki Kakinuma, Md, PhD (2010-2012)

 Irene Moy, MD (2008-2012; REI Subspecialty Fellow)

 Hideki Tokunaga, MD (2007-2009), Current position: Assistant Professor, Department of Obstetrics and Gynecology, Tohoku University School of Medicine

 Mary Ellen Pavone, MD (2007-2010)

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 Hiroshi Ishikawa, M.D., PhD, (2006-2009), Current Position: Associate Professor, Department of Obstetrics and Gynecology, Chiba University, Tokyo, Japan

 Elena Trukhacheva, MD (2006-2008; REI Subspecialty Fellow), Current Position: Private Practice, Chicago, IL

 Erica Marsh, MD (2005-2008; REI Subspecialty Fellow), Current Position: Assistant Professor, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine

 Zhihong Lin, PhD (2003-2008), Current position: Staff Scientist, Abbott Laboratories, Chicago, IL

 Qing Xue, MD, PhD (2005-2007), Current Position: Assistant Professor, Department of Obstetrics and Gynecology, First Hospital of Peking University, Beijing, China

 Emily Su, MD (2005-2007; MFM Subspecialty Fellow), Current Position: Assistant Professor, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine

 Amy Hakim, MD, MS, MA (2005-2007; Gyn-Onc Subspecialty Fellow), Current Position: Staff Physician, Department of Obstetrics and Gynecology, City of Hope Hospital, CA

 Veysel Fenkci, MD (2005-2006), Current Position: Associate Professor, Department of Obstetrics and Gynecology, Denizli University, Turkey

 Erkut Attar, MD (2005-2006), Current Position: Professor, Department of Obstetrics and Gynecology, Istanbul University, Istanbul, Turkey

 Hiroki Utsunomiya, M.D. (2003-2006), Current Position: Associate Professor, Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan

 Masashi Demura, M.D. (2003-2006), Current Position: Attending Physician, Section of General Internal Medicine, Takaoka City Hospital, Japan

 Stephen Thung, M.D. (2004-2005; MFM Subspecialty Fellow), Current position: Assistant Professor, Department of Obstetrics and Gynecology, Yale Medical School, New Haven, CN

 Ping Yin, MD, PhD (2004-2009)

 Regina Martin, M.D. (2004-2005), Current position: Assistant Professor, Department of Medicine (Endocrinology), University of Sao Paolo, Sao Paolo, Brazil

 Ayse Gonca Imir, M.D. (2003-2005), Current position: Associate Professor, Department of Obstetrics and Gynecology Cumhuriyet University, Sivas, Turkey

 Santanu Deb, Ph.D. (2002-2005), Current position: Senior Scientist, US Department of Homeland Security

 Zong juan Fang, M.D. (1998-2004), Current position: Research Assistant Professor, School of Dentistry, University of Illinois at Chicago

 Sijun Yang, M.D. (1999-2003), Current position: Research Assistant Professor, School of Dentistry, University of Illinois at Chicago

 Bilgin Gurates, M.D. (1999-2003), Current position: Associate Professor and Chairman, Department of Obstetrics and Gynecology, Elazig School of Medicine, Elazig, Turkey

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 Siby Sebastian, Ph.D. DABMG (1999-2002), Current position: Associate Professor of Pathology – Duke University Medical Center, Co-Director, Clinical Molecular Diagnostics Laboratory, Duke University Health System Clinical Laboratories, Durham, NC

 Mitsutoshi Tamura, M.D. (1999-2002), Current position: Assistant Professor, Department of Obstetrics and Gynecology, Tohoku University School of Medicine

 Jianfeng Zhou, M.D., Ph.D. (1998-2001; Hem-Onc Subspecialty Fellow), Current Position: Chairman, Department of Internal Medicine, Tongji Medical School, University of Wuhan, China

 Khaled Zeitoun, M.D. (1996-2000; REI Subspecialty Fellow), Fellow in Reproductive Endocrinology and Infertility Program of Dept. of Obstetrics-Gynecology, UT Southwestern Medical Center at Dallas (1996-1999), Dr. Zeitoun was awarded an American Association of Obstetricians and Gynecologists Fellowship grant ($144,000 award, 1998-2001) under the mentorship of Serdar E. Bulun., Current position: Assistant Professor, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York

 George Attia, MD (1998-1999; REI Subspecialty Fellow), Fellow in Reproductive Endocrinology and Infertility Program of Dept. of Obstetrics-Gynecology, UT Southwestern Medical Center at Dallas (1998-1999), Current position: Associate Professor and Director, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Miami, FL

 Hiroshi Murakami, M.D. (1998-1999), Current position: Associate Professor, Department of Surgery, Tohoku University School of Medicine, Sendai, Japan

 Makio Shozu, M.D. (1997-1998), Current position: Professor and Chair, Department of Obstetrics and Gynecology Chiba University School of Medicine, Tokyo, Japan

 Kazuto Takayama, M.D. (1995-1997), Current position: Assistant Professor, Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan

 Luis Noble, M.D. (1994-1996; REI Subspecialty Fellow), Current position: Reproductive Endocrinology, Columbia West-HCA Hospital, El Paso, Texas

 John Nichols, M.D. (1993-1995; REI Subspecialty Fellow), Current position: Reproductive Endocrinology, Greenville Hospital System, Greenville, SC.

Mentored Junior Faculty:  Mary Ellen Pavone, MD, Asst Prof (tenure track, 2008-present), NIH- K12 award (2010-2013, Mentor: Bulun)

 Erica Marsh, MD, Asst Prof (tenure track, 2008-present), Career Development (Amos) Award from the Robert Wood Johnson Foundation (2008-2012, Mentor: Bulun), NIH- K12 award (2010-2013, Mentor: Bulun)

 Emily Su, MD, Asst Prof (tenure track, 2008-present), Career Development Award from the American Association of Obstetricians and Gynecologists Foundation (2007-2010, Mentor: Bulun), NIH-K08 award (2010-2013, Mentor Bulun)

 Ping Yin, MD, PhD, Res Asst Prof (2013-present)

 Hong Zhao, PhD, Res Asst Prof (2005-present)

 You-Hong Cheng, PhD, Res Asst Prof (2004-2011)

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 Dong Chen, PhD, Res Asst Prof (2004-2012)

 Meiling Lu, PhD, Res Asst Prof (2005-2007), Current position: Res Asst Prof, Department of Pharmacology, Northwestern University

Grants: Active: 1. NIH R37 Award HD38961 Mechanisms of Estrogen Biosynthesis in Endometriosis; Principal Investigator: Serdar E. Bulun, ~$6,500,000 award, 1999-2020. 2. NIH K12 Award HD050121; Women’s Reproductive Health Research Career Development Program at Northwestern. Principal Investigator: Serdar E. Bulun, ~$4,600,000 award, 2005-2015. 3. NIH P01 Award HD057877; Uterine Leiomyoma Research Program at Northwestern; Principal Investigator: Serdar E. Bulun, ~$5,800,000 award, 2009-2014. 4. Bill and Melinda Gates Foundation Award OPP1031734; Mucus changes during the menstrual cycle and the interactions of HIV-antibody complexes with mucus. Project Leader: Serdar Bulun (PI: Thomas Hope); $300,000 award for Bulun Project (Total award ~$5,000,000) 2011-2014. 5. Lynn Sage Breast Cancer Foundation Award; Obesity, Aromatase and Breast Cancer; Principal Investigator: Serdar E. Bulun, $250,000 award, 2010-2013. 6. AVON Breast Cancer Center Research Award; Principal Investigator: Serdar E. Bulun, $1,650,000 award, 2006- 2013.

Previous: 1. Chicago Biomedical Consortium Catalyst Award; a Systems Biology Understanding of Estrogen Receptor Action; Principal Investigator at Northwestern: Serdar E. Bulun, $67,000 award, 2010-2012. (Total award 200,000, shared with Drs. Jonna Frasor and Yang Dai at UIC). 2. NIH U54 Award HD40093; Center for Women’s Health and Reproduction. Co-Director: Serdar E. Bulun, (Director: Asgi Fazleabas), ~$13,000,000 total award, 2002-2012. Hormone Action in Endometriosis. Project (2) Leader: Serdar E. Bulun, ~$3,000,000 award, 2002-2012. 3. Northwestern Medical Foundation Award; a Novel Genetically Engineered Mouse Model of Inguinal Hernia; Principal Investigator: Serdar E. Bulun, $50,000 award, 2009-2011. 4. NIH R01 Award CA67167; Breast Cancer-Proximal Stroma Interactions and Aromatase; Principal Investigator: Serdar E. Bulun, ~$3,900,000 award, 1996-2011. 5. AVON Foundation Award; Regulation of Aromatase Expression by Tumor Suppressor Gene BRCA; Principal Investigator: Serdar E. Bulun, $25,000 award, 2007-2008 6. NIH R01 Award HD46260; Estrogen Biosynthesis and Uterine Leiomyomata; Principal Investigator: Serdar E. Bulun, $1,118,000 award, 2003-2008. 7. Northwestern Memorial Foundation; Development of Breast Cancer–Specific Aromatase Inhibitors; Principal Investigator: Serdar E. Bulun, $41,666 award, 2006-2007. 8. Northwestern Memorial Foundation; Aromatase as a Therapeutic Target for Breast Cancer; Principal Investigator: Serdar E. Bulun, $660,000 award, 2004-2007. 9. Lynn Sage Award, State of Illinois Department of Public Health; Breast Cancer-Proximal Stroma Interactions and Aromatase; Principal Investigator: Serdar E. Bulun, $25,000 award, 2005-2006. 10. NIH-NCI P50 Award CA89018, SPORE in Breast Cancer – Pilot Project: Gene Profiling by Microarray for Discovery of Molecular Predictors of Response to Aromatase Inhibitors in Breast Tumors. Principal Investigator: Serdar E. Bulun, $50,000 award 2005-2006. 11. NIH-NCI P50 Award CA89018, SPORE in Breast Cancer; Principal Investigator: Serdar E. Bulun, $14,095,240 award 2004-2006. (S Bulun became the PI upon departure of the original PI, C Jordan in 2004.) 12. NIH-NCI P30 Award CA060553, Robert H. Lurie Comprehensive Cancer Center, Co-Leader, Women’s Cancers: Serdar E. Bulun (PI: S Rosen), $4,643,206 award, 2001-2006. 13. Intercampus Research Initiative in Biotechnology; University of Illinois, Affymetrix Technology Platform for the Genomic Analysis of Women’s Neoplasms; Co-Investigator (Principal Investigator: Carol Westbrook), $450,000

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award, 2001-2004. 14. Novartis, Pharma; Treatment of Endometriosis with an Aromatase Inhibitor Principal Investigator: Serdar E. Bulun, $130,000 award, 2001-2003. 15. Astra-Zeneca; Treatment of Endometriosis with an Aromatase Inhibitor; Principal Investigator: Serdar E. Bulun, $100,000 award, 2001-2003. 16. NIH R03 Award TW01339; Mechanisms of Infertility in Endometriosis; Principal Investigator: Serdar E. Bulun, $191,833 award, 2000-2003. 17. US Army Breast Cancer Research Idea Award DAMD17-97-1-7025; Adipocyte Differentiation: Relationship to Breast Cancer; Principal Investigator: Serdar E. Bulun, $300,000 award, 1997-2002. 18. American Association of Obstetricians and Gynecologists Foundation (AAOGF) Fellowship Award; Molecular Basis for Estrogen Biosynthesis in Endometriosis: A Target for Novel Treatment Strategies; Principal Investigator: Khaled Zeitoun; Sponsor: Serdar E. Bulun, $144,000 award, 1998-2001. 19. University of Illinois Center Seed Grant Initiative; Endometriosis: Basic and Clinical Aspects; Co-Director: Serdar E. Bulun, $100,000 award, 1999-2000. 20. American Society for Reproductive Medicine and Organon Unrestricted Research Grant; Development of Molecular Markers for Endometriosis; Principal Investigator: Serdar E. Bulun, $20,000 award, 1997-1998 21. US Army Career Development Award DAMD17-94-J-4188; Breast Cancer and Estrogen Biosynthesis in Adipose Tissue; Principal Investigator: Serdar E. Bulun, $200,000 award, 1994-1998. 22. Zonagen, Inc., (Houston, Texas) Research Grant; Aromatase Expression in Human Endometrium; Principal Investigator: Serdar E. Bulun, $65,503 award, 1996-1997. 23. American Association of Obstetricians and Gynecologists Foundation (AAOGF) Fellowship Award; Aromatase Enzyme and Breast Cancer; Principal Investigator: Serdar E. Bulun, $96,000 award, 1994-1996 24. Society for Gynecologic Investigation-Mead Johnson Unrestricted Research Grant; Aromatase Expression in Endocrine-Responsive Tumors; Principal Investigator: Serdar E. Bulun, $15,000 award, 1993.

Patents: 1. U.S. Patent 7,910,570.Composition comprising a combination of an aromatase inhibitor, a progestin and an estrogen and its use for the treatment of endometriosis. Rubin S, Bulun SE. 2. U.S. Patent Pending (application 61/491,743) SUSD3 as a target for prevention, diagnosis, and treatment of estrogen/progesterone-dependent disorders. Moy I, Bulun SE.

Scholarly Bibliography: Peer Reviewed Papers:

1. Bulun SE. Ovarian endometriosis: the nemesis of eggs. Fertil Steril. 2014. In press. 2. Dyson MT, Roquerio D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, Kakinuma T, Ono, M, Jafari N, Dai Y, Bulun SE. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLOS Genetics. 2014. 10(3): e1004158. 3. Xue Q, Xu Y, Yang H, Zhang L, Shang J, Zeng C, Yin P, Bulun SE. Methyation of a novel CpG island of intron 1 is associated with steroidogenic factor 1 expression in endometriotic stromal cells. Reprod Sci. 2014 Mar; 21(3):395- 400. doi: 10.1177/1933719113497283. PMID: 23899549. 4. Ono M, Yin P, Navarro A, Moravek MB, Coon V JS, Druschitz SA, Gottardi CJ, Bulun SE: Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth. Fertil Steril. 2014 Feb 14. pii:S0015-0282(14)00048-X. PMID: 24534281 5. Bulun SE. Aromatase and estrogen receptor a deficiency. Fertil Steril. 2014Feb;101(2):323-9. PMID: 24485503 6. Bulun SE. Uterine Fibroids. N Engl J. Med. 2013 Oct 3;369(14):1344-1355. PMID: 24088094. 7. Ono M, Yin P, Navarro A, Moravek MB, Coon JS 5th Druschitz SA, Serna VA, Qiang W, Brooks DC, Malpani SS, Ma J, Ercan CM, Mittal N, Monsivais D, Dyson MT, Yemelyanov A, Maruyama T, Chakravarti D, Kim JJ, Kurita T, Gottardi CJ, Bulun SE. Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc Natl Acad Sci U S A. 2013 Sep 30. PMID 24082114.

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8. Fukami M, Tsuchiya T, Vollbach H, Brown KA, Abe S, Ohtsu S, Wabitsch M, Burger H, Simpson ER, Umezawa A, Shihara D, Nakabayashi K, Bulun SE, Shozu M, Ogata T. Genomic Basis of Aromatase Excess Syndrome: Recombination-and-replication-mediated rearrangements leading to cyp19a1 overexpression. J Clin Endocrinol Metab.2013 Sep 24. 9. Ma JJ, Monsivais D, Dyson MT, Coon JS, Malpani S, Ono M, Zhao H, Xin H, Pavone ME, Kim JJ, Chakravarti D, Bulun SE. Ligand-activated peroxisome proliferator-activated receptor β/δ modulates human endometrial cancer Cell Survival. Horm Cancer. 2013 Aug 14. ue Q, Yu Y, Yang H, Zhang, L, Shang J, Zeng C, Yin P, Bulun SE. Reprod Sci. 2013 Jul 30. PMID: 23899549 10. Bulun SE. Semin Reprod Med. 2013 May; 31(3):185. doi: 10.1055/s-0033-1336597. Epub 2013 Apr 22. No abstract available. PMID: 23609147. 11. Yin H, Lo JH, Kim JY, Marsh EE, Kim JJ, Ghosh AK, Bulun SE, Chakravarti D: Mol Endocrinol. 2013 May;27(5):726-40. doi: 10.1210/me.2012-1305. PMID: 23550059. 12. Pavone ME, Bulun SE. Clinical review: The use of aromatase inhibitors for ovulation induction and superovulation. J Clin Endocrinol Metab. 2013 May; 98(5):1838-44. doi:10.1210/jc.2013-1328. Epub 2013 Apr 12, Review. PMID:23595659. 13. Kim JJ, Kurita T, Bulun SE. Progesterone action in endometrial cancer, Endometriosis, Uterine Fibroids, and Breast Cancer. Endocr Rev. 2013 Jan 9. PubMed PMID: 23303565. 14. Langoi D, Pavone ME, Gurates B, Chai D, Fazleabas A, Bulun SE. Aromatase inhibitor treatment may limit progression of peritoneal endometriosis in baboons. Fertil Steril. 2012 Dec 17. PMID: 23257603. 15. Fukami M, Tsuchiya T, Vollbach H, Brown KA, Abe S, Ohtsu S, Wabitsch M, Burger H, Simpson ER, Umezawa A, Shihara D, Nakabayashi K, Bulun SE, 16. Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis. Fertil Steril. 2012 Sep 19. PMID: 22999792. 17. Dyson MT, Bulun SE. Cutting SRC-1 down to size in endometriosis. Nat Med. 2012 Jul 6;18(7):1016-8. PubMed PMID: 22772552. 18. Brooks DC, Zhao H, Yilmaz MB, Coon V JS, Bulun SE. Glucocorticoid-induction of hypothalamic aromatase via its brain-specific promoter. Mol Cell Endocrinol. 2012 Oct 15;362(1-2):85-90. Epub 2012 Jun 13. PubMed PMID: 22705581; PubMed Central PMCID: PMC3434699. 19. Ono M, Qiang W, Serna VA, Yin P, Coon JS 5th, Navarro A, Monsivais D, Kakinuma T, Dyson M, Druschitz S, Unno K, Kurita T, Bulun SE. Role of stem cells in human uterine leiomyoma growth. PLoS One. 2012;7(5):e36935. Epub 2012 May 3. PubMed PMID: 22570742; PubMed Central PMCID: PMC3343011. 20. Monsivais D, Bray JD, Su E, Pavone ME, Dyson MT, Navarro A, Kakinuma T, Bulun SE. Activated glucocorticoid and eicosanoid pathways in endometriosis. Fertil Steril. 2012 Jul;98(1):117-25. Epub 2012 Apr 21. PubMed PMID: 22521153; PubMed Central PMCID: PMC3389283. 21. Zhao H, Pearson EK, Brooks DC, Coon JS 5th, Chen D, Demura M, Zhang M, Clevenger CV, Xu X, Veenstra TD, Chatterton RT, DeMayo FJ, Bulun SE. A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice. Endocrinology. 2012 Jun;153(6):2701-13. Epub 2012 Apr 16. PubMed PMID: 22508516; PubMed Central PMCID: PMC3359608. 22. Navarro A, Yin P, Monsivais D, Lin SM, Du P, Wei JJ, Bulun SE. Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One. 2012;7(3):e33284. Epub 2012 Mar 13. PubMed PMID: 22428009; PubMed Central PMCID: PMC3302826. 23. Chen D, Zhao H, Coon JS 5th, Ono M, Pearson EK, Bulun SE. Weight gain increases human aromatase expression in mammary gland. Mol Cell Endocrinol. 2012 May 15;355(1):114-20. Epub 2012 Feb 10. PubMed PMID: 22342815; PubMed Central PMCID: PMC3312968. 24. Yin P, Roqueiro D, Huang L, Owen JK, Xie A, Navarro A, Monsivais D, Coon JS 5th, Kim JJ, Dai Y, Bulun SE. Genome-wide progesterone receptor binding: cell type-specific and shared mechanisms in T47D breast cancer cells and primary leiomyoma cells. PLoS One. 2012;7(1):e29021. Epub 2012 Jan 17. PubMed PMID: 22272226; PubMed Central PMCID: PMC3260146. 25. Bulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, Tokunaga H, Su EJ. Role of estrogen receptor-β in endometriosis. Semin Reprod Med. 2012 Jan;30(1):39-45. Epub 2012 Jan 23. Review. PubMed PMID: 22271293. 26. Bulun SE, Chen D, Moy I, Brooks DC, Zhao H. Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab. 2012 Feb;23(2):83-9.Epub 2011 Dec 12. Review. PubMed PMID: 22169755; PubMed Central PMCID: PMC3428377. 27. Xue Q, Zhou YF, Zhu SN, Bulun SE. Hypermethylation of the CpG island spanning from exon II to intron III is

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associated with steroidogenic factor 1 expression in stromal cells of endometriosis. Reprod Sci. 2011 Nov;18(11):1080-4. Epub 2011 Sep 16. PubMed PMID: 21926385; PubMed Central PMCID: PMC3343144. 28. Abushahin F, Goldman KN, Barbieri E, Milad M, Rademaker A, Bulun SE. Aromatase inhibition for refractory endometriosis-related chronic pelvic pain. Fertil Steril. 2011 Oct;96(4):939-42. Epub 2011 Aug 24. Erratum in: Fertil Steril. 2012 Apr;97(4):1017. PubMed PMID: 21868006. 29. Su EJ, Ernst L, Abdallah N, Chatterton R, Xin H, Monsivais D, Coon J, Bulun SE. Estrogen receptor-β and fetoplacental endothelial prostanoid biosynthesis: a link to clinically demonstrated fetal growth restriction. J Clin Endocrinol Metab. 2011 Oct;96(10):E1558-67. Epub 2011 Aug 10. PubMed PMID: 21832119; PubMed Central PMCID: PMC3200254. 30. Yin P, Navarro A, Fang F, Xie A, Coon JS, Richardson C, Bulun SE. Early growth response-2 expression in uterine leiomyoma cells: regulation and function. Fertil Steril. 2011 Aug;96(2):439-44. Epub 2011 Jun 24. PubMed PMID: 21703609; PubMed Central PMCID: PMC3143242. 31. Pavone ME, Dyson M, Reirstad S, Pearson E, Ishikawa H, Cheng YH, Bulun SE. Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action. Hum Reprod. 2011 Aug;26(8):2157-64. Epub 2011 Jun 8. PubMed PMID: 21659316; PubMed Central PMCID: PMC3137392. 32. Yilmaz MB, Wolfe A, Zhao H, Brooks DC, Bulun SE. Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines. J Mol Endocrinol. 2011 Jul 18;47(1):69-80. Print 2011 Aug. PubMed PMID: 21628418. 33. Chen D, Reierstad S, Fang F, Bulun SE. JunD and JunB integrate prostaglandin E2 activation of breast cancer- associated proximal aromatase promoters. Mol Endocrinol. 2011 May;25(5):767-75. Epub 2011 Mar 10. PubMed PMID: 21393445; PubMed Central PMCID: PMC3082330. 34. Demura M, Demura Y, Ameshima S, Ishizaki T, Sasaki M, Miyamori I, Yamagishi M, Takeda Y, Bulun SE. Changes in aromatase (CYP19) gene promoter usage in non-small cell lung cancer. Lung Cancer. 2011 Sep;73(3):289-93. Epub 2011 Feb 12. PubMed PMID: 21320735; PubMed Central PMCID: PMC3118270. 35. Cheng YH, Utsunomiya H, Pavone ME, Yin P, Bulun SE. Retinoic acid inhibits endometrial cancer cell growth via multiple genomic mechanisms. J Mol Endocrinol. 2011 Mar 23;46(2):139-53. Print 2011 Apr. PubMed PMID: 21310893. 36. Pavone ME, Reierstad S, Sun H, Milad M, Bulun SE, Cheng YH. Altered retinoid uptake and action contributes to cell survival in endometriosis. J Clin Endocrinol Metab. 2010 Nov;95(11):E300-9. Epub 2010 Aug 11. PubMed PMID: 20702525; PubMed Central PMCID: PMC2968735. 37. Xia Luo, Coon JS 5th, Su E, Pearson EK, Ping Yin, Ishikawa H, Bulun SE. LAT1 regulates growth of uterine leiomyoma smooth muscle cells. Reprod Sci. 2010 Sep;17(9):791-7. Epub 2010 Jul 2. PubMed PMID: 20601542. 38. Ishikawa H, Ishi K, Serna VA, Kakazu R, Bulun SE, Kurita T. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology. 2010 Jun;151(6):2433-42. Epub 2010 Apr 7. PubMed PMID: 20375184; PubMed Central PMCID: PMC2875812. 39. Yin P, Lin Z, Reierstad S, Wu J, Ishikawa H, Marsh EE, Innes J, Cheng Y, Pearson K, Coon JS 5th, Kim JJ, Chakravarti D, Bulun SE. Transcription factor KLF11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells. Cancer Res. 2010 Feb 15;70(4):1722-30. Epub 2010 Feb 2. PubMed PMID: 20124487; PubMed Central PMCID: PMC2822899. 40. Bulun SE, Cheng YH, Pavone ME, Yin P, Imir G, Utsunomiya H, Thung S, Xue Q, Marsh EE, Tokunaga H, Ishikawa H, Kurita T, Su EJ. 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis. Semin Reprod Med. 2010 Jan;28(1):44-50. Review. PubMed PMID: 20108182. 41. Bulun SE, Cheng YH, Pavone ME, Xue Q, Attar E, Trukhacheva E, Tokunaga H, Utsunomiya H, Yin P, Luo X, Lin Z, Imir G, Thung S, Su EJ, Kim JJ. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010 Jan;28(1):36-43. Epub 2010 Jan 26. Review. PubMed PMID: 20104427; PubMed Central PMCID: PMC3073375. 42. Bulun SE. Progesterone resistance and endometrial disease. Preface. Semin Reprod Med. 2010 Jan;28(1):3. Epub 2010 Jan 26. PubMed PMID: 20104423. 43. Luo X, Yin P, Coon V JS, Cheng YH, Wiehle RD, Bulun SE. The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells. Fertil Steril. 2010 May 15;93(8):2668-73. Epub 2010 Jan 8. PubMed PMID: 20056218; PubMed Central PMCID: PMC2872031. 44. Lin Z, Yin P, Reierstad S, O'Halloran M, Coon VJ, Pearson EK, Mutlu GM, Bulun SE. Adenosine A1 receptor, a target and regulator of estrogen receptoralpha action, mediates the proliferative effects of estradiol in breast cancer.

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Oncogene. 2010 Feb 25;29(8):1114-22. Epub 2009 Nov 23. PubMed PMID: 19935720; PubMed Central PMCID: PMC2829108. 45. Luo X, Yin P, Reierstad S, Ishikawa H, Lin Z, Pavone ME, Zhao H, Marsh EE, Bulun SE. Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells. J Clin Endocrinol Metab. 2009 Nov;94(11):4533-9. Epub 2009 Oct 6. PubMed PMID: 19808856; PubMed Central PMCID: PMC2775649. 46. Mesquita FS, Dyer SN, Heinrich DA, Bulun SE, Marsh EE, Nowak RA. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol Reprod. 2010 Feb;82(2):341-51. Epub 2009 Sep 9. PubMed PMID: 19741209; PubMed Central PMCID: PMC2809225. 47. Yilmaz MB, Wolfe A, Cheng YH, Glidewell-Kenney C, Jameson JL, Bulun SE. Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines. Biol Reprod. 2009 Nov;81(5):956-65. Epub 2009 Jul 15. PubMed PMID: 19605792. 48. Lin BC, Suzawa M, Blind RD, Tobias SC, Bulun SE, Scanlan TS, Ingraham HA. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res. 2009 Jul 1;69(13):5415-23. Epub 2009 Jun 23. PubMed PMID: 19549922; PubMed Central PMCID: PMC2756996. 49. Zhao H, Innes J, Brooks DC, Reierstad S, Yilmaz MB, Lin Z, Bulun SE. A novel promoter controls Cyp19a1 gene expression in mouse adipose tissue. Reprod Biol Endocrinol. 2009 Apr 24;7:37. PubMed PMID: 19393092; PubMed Central PMCID: PMC2684739. 50. Su EJ, Lin ZH, Zeine R, Yin P, Reierstad S, Innes JE, Bulun SE. Estrogen receptor-beta mediates cyclooxygenase- 2 expression and vascular prostanoid levels in human placental villous endothelial cells. Am J Obstet Gynecol. 2009 Apr;200(4):427.e1-8. PubMed PMID: 19318151. 51. Guo SW, Hummelshoj L, Olive DL, Bulun SE, D'Hooghe TM, Evers JL. A call for more transparency of registered clinical trials on endometriosis. Hum Reprod. 2009 Jun;24(6):1247-54. Epub 2009 Mar 4. Review. PubMed PMID: 19264712. 52. Ishikawa H, Reierstad S, Demura M, Rademaker AW, Kasai T, Inoue M, Usui H, Shozu M, Bulun SE. High aromatase expression in uterine leiomyoma tissues of African-American women. J Clin Endocrinol Metab. 2009 May;94(5):1752-6. Epub 2009 Feb 24. PubMed PMID: 19240151; PubMed Central PMCID: PMC2684481. 53. Bulun SE, Utsunomiya H, Lin Z, Yin P, Cheng YH, Pavone ME, Tokunaga H, Trukhacheva E, Attar E, Gurates B, Milad MP, Confino E, Su E, Reierstad S, Xue Q. Steroidogenic factor-1 and endometriosis. Mol Cell Endocrinol. 2009 Mar 5;300(1-2):104-8. Epub 2008 Dec 25. Review. PubMed PMID: 19150483. 54. Bulun SE. Endometriosis. N Engl J Med. 2009 Jan 15;360(3):268-79. Review. PubMed PMID: 19144942. 55. Luo X, Yin P, Reierstad S, Ishikawa H, Lin Z, Pavone ME, Zhao H, Marsh EE, Bulun SE. Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells. J Clin Endocrinol Metab. 2009 Nov;94(11):4533-9. Epub 2009 Oct 6. PubMed PMID: 19808856; PubMed Central PMCID: PMC2775649. 56. Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, Gurates B, Attar R, Yaegashi N, Hales DB, Bulun SE. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009 Feb;94(2):623-31. Epub 2008 Nov 11. PubMed PMID: 19001523; PubMed Central PMCID: PMC2646521. 57. Trukhacheva E, Lin Z, Reierstad S, Cheng YH, Milad M, Bulun SE. Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis. J Clin Endocrinol Metab. 2009 Feb;94(2):615-22. Epub 2008 Nov 11. PubMed PMID: 19001520; PubMed Central PMCID: PMC2646522. 58. Demura M, Reierstad S, Innes JE, Bulun SE. Novel promoter I.8 and promoter usage in the CYP19 (aromatase) gene. Reprod Sci. 2008 Dec;15(10):1044-53. Epub 2008 Oct 27. PubMed PMID: 18955734. 59. Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SE. Regulation of breast cancer-associated aromatase promoters. Cancer Lett. 2009 Jan 8;273(1):15-27. Epub 2008 Jul 9. Review. PubMed PMID: 18614276. 60. Ishikawa H, Fenkci V, Marsh EE, Yin P, Chen D, Cheng YH, Reisterd S, Lin Z, Bulun SE. CCAAT/enhancer binding protein beta regulates aromatase expression via multiple and novel cis-regulatory sequences in uterine leiomyoma. J Clin Endocrinol Metab. 2008 Mar;93(3):981-91. Epub 2008 Jan 8. Erratum in: J Clin Endocrinol Metab. 2009 Apr;94(4):1476. Fencki, Veysel [corrected to Fenkci, Veysel]. PubMed PMID: 18182446; PubMed Central PMCID: PMC2266947. 61. Utsunomiya H, Cheng YH, Lin Z, Reierstad S, Yin P, Attar E, Xue Q, Imir G, Thung S, Trukhacheva E, Suzuki T, Sasano H, Kim JJ, Yaegashi N, Bulun SE. Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis. Mol Endocrinol. 2008 Apr;22(4):904-14. Epub 2007 Dec 28. PubMed PMID:

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18165439; PubMed Central PMCID: PMC2276471. 62. Chen D, Reierstad S, Lin Z, Lu M, Brooks C, Li N, Innes J, Bulun SE. Prostaglandin E(2) induces breast cancer related aromatase promoters via activation of p38 and c-Jun NH(2)-terminal kinase in adipose fibroblasts. Cancer Res. 2007 Sep 15;67(18):8914-22. PubMed PMID: 17875734. 63. Yin P, Lin Z, Cheng YH, Marsh EE, Utsunomiya H, Ishikawa H, Xue Q, Reierstad S, Innes J, Thung S, Kim JJ, Xu E, Bulun SE. Progesterone receptor regulates Bcl-2 gene expression through direct binding to its promoter region in uterine leiomyoma cells. J Clin Endocrinol Metab. 2007 Nov;92(11):4459-66. Epub 2007 Sep 4. PubMed PMID: 17785366. 64. Marsh EE, Lin Z, Yin P, Milad M, Chakravarti D, Bulun SE. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril. 2008 Jun;89(6):1771-6. Epub 2007 Sep 4. PubMed PMID: 17765232; PubMed Central PMCID: PMC2773156. 65. Xue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, Milad MP, Confino E, Reierstad S, Innes J, Bulun SE. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod. 2007 Oct;77(4):681-7. Epub 2007 Jul 11. PubMed PMID: 17625110. 66. Demura M, Martin RM, Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K, Bryant M, Mendonca BB, Hanaki K, Kanzaki S, Rhoads DB, Misra M, Bulun SE. Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. Hum Mol Genet. 2007 Nov 1;16(21):2529-41. Epub 2007 Jun 21. PubMed PMID: 17584767. 67. Su EJ, Cheng YH, Chatterton RT, Lin ZH, Yin P, Reierstad S, Innes J, Bulun SE. Regulation of 17-beta hydroxysteroid dehydrogenase type 2 in human placental endothelial cells. Biol Reprod. 2007 Sep;77(3):517-25. Epub 2007 May 30. PubMed PMID: 17538076. 68. Xue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, Reierstad S, Bulun SE. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5' CpG island in endometriosis. J Clin Endocrinol Metab. 2007 Aug;92(8):3261-7. Epub 2007 May 22. PubMed PMID: 17519303. 69. Lin Z, Reierstad S, Huang CC, Bulun SE. Novel estrogen receptor-alpha binding sites and estradiol target genes identified by chromatin immunoprecipitation cloning in breast cancer. Cancer Res. 2007 May 15;67(10):5017-24. PubMed PMID: 17510434. 70. Cheng YH, Imir A, Fenkci V, Yilmaz MB, Bulun SE. Stromal cells of endometriosis fail to produce paracrine factors that induce epithelial 17beta-hydroxysteroid dehydrogenase type 2 gene and its transcriptional regulator Sp1: a mechanism for defective estradiol metabolism. Am J Obstet Gynecol. 2007 Apr;196(4):391.e1-7; discussion 391.e7- 8. PubMed PMID: 17403431. 71. Imir AG, Lin Z, Yin P, Deb S, Yilmaz B, Cetin M, Cetin A, Bulun SE. Aromatase expression in uterine leiomyomata is regulated primarily by proximal promoters I.3/II. J Clin Endocrinol Metab. 2007 May;92(5):1979-82. Epub 2007 Mar 6. PubMed PMID: 17341559. 72. Lu M, Chen D, Lin Z, Reierstad S, Trauernicht AM, Boyer TG, Bulun SE. BRCA1 negatively regulates the cancer- associated aromatase promoters I.3 and II in breast adipose fibroblasts and malignant epithelial cells. J Clin Endocrinol Metab. 2006 Nov;91(11):4514-9. Epub 2006 Aug 29. PubMed PMID: 16940443. 73. Cheng YH, Imir A, Suzuki T, Fenkci V, Yilmaz B, Sasano H, Bulun SE. SP1 and SP3 mediate progesterone- dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14. Epub 2006 Jun 28. PubMed PMID: 16807381. 74. Amin SA, Huang CC, Reierstad S, Lin Z, Arbieva Z, Wiley E, Saborian H, Haynes B, Cotterill H, Dowsett M, Bulun SE. Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. Mol Cell Endocrinol. 2006 Jul 11;253(1-2):44-55. Epub 2006 Jun 2. PubMed PMID: 16735089. 75. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril. 2006 May;85(5):1307-18. Review. PubMed PMID: 16647373. 76. Bulun SE, Cheng YH, Yin P, Imir G, Utsunomiya H, Attar E, Innes J, Julie Kim J. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006 Mar 27;248(1-2):94-103. Epub 2006 Jan 10. Review. PubMed PMID: 16406281. 77. Deb S, Zhou J, Amin SA, Imir AG, Yilmaz MB, Lin Z, Bulun SE. A novel role of sodium butyrate in the regulation of cancer-associated aromatase promoters I.3 and II by disrupting a transcriptional complex in breast adipose fibroblasts. J Biol Chem. 2006 Feb 3;281(5):2585-97. Epub 2005 Nov 21. Erratum in: J Biol Chem. 2006 Apr 7;281(14):9832. Jianfeng, Zhou [corrected to Zhou, Jianfeng]; Gonca, Imir Ayse [corrected to Imir, Ayse Gonca]; Bertan, Yilmaz Mehmet [corrected to Yilmaz, Mehmet Bertan]; Zihong, Lin [corrected to Lin, Zhihong]. PubMed

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PMID: 16303757. 78. Attar E, Bulun SE. Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum Reprod Update. 2006 Jan-Feb;12(1):49-56. Epub 2005 Aug 25. Review. PubMed PMID: 16123052. 79. Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005 Sep;57(3):359-83. Review. PubMed PMID: 16109840. 80. Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, Bulun SE. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril. 2005 Aug;84(2):300-4. PubMed PMID: 16084868. 81. Fang Z, Yang S, Lydon JP, DeMayo F, Tamura M, Gurates B, Bulun SE. Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis. Fertil Steril. 2004 Sep;82(3):673-8. PubMed PMID: 15374713. 82. Deb S, Amin S, Imir AG, Yilmaz MB, Suzuki T, Sasano H, Bulun SE. Estrogen regulates expression of tumor necrosis factor receptors in breast adipose fibroblasts. J Clin Endocrinol Metab. 2004 Aug;89(8):4018-24. PubMed PMID: 15292343. 83. Tamura M, Deb S, Sebastian S, Okamura K, Bulun SE. Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterine microvascular endothelial cells. Fertil Steril. 2004 May;81(5):1351-6. PubMed PMID: 15136101. 84. Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, Langoi D, Amin S, Yang S, Deb S. Aromatase and endometriosis. Semin Reprod Med. 2004 Feb;22(1):45-50. Review. PubMed PMID: 15083380. 85. Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S. Organization of the human aromatase p450 (CYP19) gene. Semin Reprod Med. 2004 Feb;22(1):5-9. Review. PubMed PMID: 15083376. 86. Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril. 2004 Feb;81(2):290-6. PubMed PMID: 14967362. 87. Bulun SE. Ovulation induction in women with infertility: a new indication for aromatase inhibitors. Fertil Steril. 2003 Dec;80(6):1338; discussion 1339. PubMed PMID: 14667864. 88. Gurates B, Amsterdam A, Tamura M, Yang S, Zhou J, Fang Z, Amin S, Sebastian S, Bulun SE. WT1 and DAX-1 regulate SF-1-mediated human P450arom gene expression in gonadal cells. Mol Cell Endocrinol. 2003 Oct 31;208(1-2):61-75. PubMed PMID: 14580722. 89. Fazleabas AT, Brudney A, Chai D, Langoi D, Bulun SE. Steroid receptor and aromatase expression in baboon endometriotic lesions. Fertil Steril. 2003 Sep;80 Suppl 2:820-7. PubMed PMID: 14505759. 90. Gurates B, Bulun SE. Endometriosis: the ultimate hormonal disease. Semin Reprod Med. 2003 May;21(2):125-34. Review. PubMed PMID: 12917782. 91. Tamura M, Sebastian S, Yang S, Gurates B, Fang Z, Okamura K, Bulun SE. Induction of cyclooxygenase-2 in human endometrial stromal cells by malignant endometrial epithelial cells: evidence for the involvement of extracellularly regulated kinases and CCAAT/enhancer binding proteins. J Mol Endocrinol. 2003 Aug;31(1):95-104. PubMed PMID: 12914528. 92. Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K, Bryant M, Bulun SE. Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. N Engl J Med. 2003 May 8;348(19):1855-65. PubMed PMID: 12736278. 93. Sebastian S, Takayama K, Shozu M, Bulun SE. Cloning and characterization of a novel endothelial promoter of the human CYP19 (aromatase P450) gene that is up-regulated in breast cancer tissue. Mol Endocrinol. 2002 Oct;16(10):2243-54. PubMed PMID: 12351690. 94. Gurates B, Sebastian S, Yang S, Zhou J, Tamura M, Fang Z, Suzuki T, Sasano H, Bulun SE. WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells. J Clin Endocrinol Metab. 2002 Sep;87(9):4369-77. PubMed PMID: 12213901. 95. Tamura M, Sebastian S, Gurates B, Yang S, Fang Z, Bulun SE. Vascular endothelial growth factor up-regulates cyclooxygenase-2 expression in human endothelial cells. J Clin Endocrinol Metab. 2002 Jul;87(7):3504-7. PubMed PMID: 12107271. 96. Fang Z, Yang S, Gurates B, Tamura M, Simpson E, Evans D, Bulun SE. Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue. J Clin Endocrinol Metab. 2002 Jul;87(7):3460-6. PubMed PMID: 12107266. 97. Tamura M, Sebastian S, Yang S, Gurates B, Fang Z, Bulun SE. Interleukin-1beta elevates cyclooxygenase-2 protein level and enzyme activity via increasing its mRNA stability in human endometrial stromal cells: an effect

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mediated by extracellularly regulated kinases 1 and 2. J Clin Endocrinol Metab. 2002 Jul;87(7):3263-73. PubMed PMID: 12107235. 98. Tamura M, Sebastian S, Yang S, Gurates B, Ferrer K, Sasano H, Okamura K, Bulun SE. Up-regulation of cyclooxygenase-2 expression and prostaglandin synthesis in endometrial stromal cells by malignant endometrial epithelial cells. A paracrine effect mediated by prostaglandin E2 and nuclear factor-kappa B. J Biol Chem. 2002 Jul 19;277(29):26208-16. Epub 2002 May 10. PubMed PMID: 12006564. 99. Yang S, Fang Z, Gurates B, Tamura M, Miller J, Ferrer K, Bulun SE. Stromal PRs mediate induction of 17beta- hydroxysteroid dehydrogenase type 2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of E2. Mol Endocrinol. 2001 Dec;15(12):2093-105. PubMed PMID: 11731611. 100. Sebastian S, Bulun SE. A highly complex organization of the regulatory region of the human CYP19 (aromatase) gene revealed by the Human Genome Project. J Clin Endocrinol Metab. 2001 Oct;86(10):4600-2. PubMed PMID: 11600509. 101. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001 Sep;45(3 Suppl):S116-24. Review. PubMed PMID: 11511861. 102. Bulun SE. Aromatase deficiency and estrogen resistance: from molecular genetics to clinic. Semin Reprod Med. 2000;18(1):31-9. Review. PubMed PMID: 11305285. 103. Zhou J, Gurates B, Yang S, Sebastian S, Bulun SE. Malignant breast epithelial cells stimulate aromatase expression via promoter II in human adipose fibroblasts: an epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein beta. Cancer Res. 2001 Mar 1;61(5):2328-34. PubMed 104. PMID: 11280806. 105. Meng L, Zhou J, Sasano H, Suzuki T, Zeitoun KM, Bulun SE. Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: 106. mechanism of desmoplastic reaction. Cancer Res. 2001 Mar 1;61(5):2250-5. PubMed PMID: 11280794. 107. Bulun SE, Zeitoun KM, Takayama K, Sasano H. Molecular basis for treating endometriosis with aromatase inhibitors. Hum Reprod Update. 2000 Sep-Oct;6(5):413-8. PubMed PMID: 11045871. 108. Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000 Aug;85(8):2897-902. PubMed PMID: 10946900. 109. Bulun SE, Zeitoun KM, Takayama K, Sasano H. Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance. J Mol Endocrinol. 2000 Aug;25(1):35-42. Review. PubMed PMID: 10915216. 110. Bulun SE, Zeitoun K, Sasano H, Simpson ER. Aromatase in aging women. Semin Reprod Endocrinol. 1999;17(4):349-58. Review. PubMed PMID: 10851574. 111. Bulun SE, Zeitoun KM, Kilic G. Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. Am J Obstet Gynecol. 2000 Apr;182(4):767-75. PubMed PMID: 10764452. 112. Bulun SE, Zeitoun K, Takayama K, Noble L, Michael D, Simpson E, Johns A, Putman M, Sasano H. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999 Jun;6(2):293-301. Review. PubMed PMID: 10731122. 113. Bulun SE, Zeitoun KM, Takayama K, Simpson E, Sasano H. Aromatase as a therapeutic target in endometriosis. Trends Endocrinol Metab. 2000 Jan-Feb;11(1):22-7. Review. PubMed PMID: 10652502. 114. Zeitoun KM, Bulun SE. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril. 1999 Dec;72(6):961-9. Review. PubMed PMID: 10593363. 115. Zeitoun K, Takayama K, Michael MD, Bulun SE. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element. Mol Endocrinol. 1999 Feb;13(2):239-53. PubMed PMID: 9973254. 116. Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab. 1998 Dec;83(12):4474-80. PubMed PMID: 9851796. 117. Agarwal VR, Takayama K, Van Wyk JJ, Sasano H, Simpson ER, Bulun SE. Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma. J Clin Endocrinol Metab. 1998 May;83(5):1797-800. PubMed PMID: 9589695. 118. Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE. Treatment of severe postmenopausal

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endometriosis with an aromatase inhibitor. Fertil Steril. 1998 Apr;69(4):709-13. PubMed PMID: 9548162. 119. Shozu M, Zhao Y, Bulun SE, Simpson ER. Multiple splicing events involved in regulation of human aromatase expression by a novel promoter, I.6. Endocrinology. 1998 Apr;139(4):1610-7. PubMed PMID: 9528941. 120. Bulun SE: The Syndrome of Aromatase Deficiency. Current Opinion in Endocrinology and Diabetes. 1998. 5:350- 356. 121. Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab. 1997 Feb;82(2):600-6. PubMed PMID: 9024261. 122. Agarwal VR, Ashanullah CI, Simpson ER, Bulun SE. Alternatively spliced transcripts of the aromatase cytochrome P450 (CYP19) gene in adipose tissue of women. J Clin Endocrinol Metab. 1997 Jan;82(1):70-4. PubMed PMID: 8989235. 123. Sasano H, Frost AR, Saitoh R, Harada N, Poutanen M, Vihko R, Bulun SE, Silverberg SG, Nagura H. Aromatase and 17 beta-hydroxysteroid dehydrogenase type 1 in human breast carcinoma. J Clin Endocrinol Metab. 1996 Nov;81(11):4042-6. PubMed PMID: 8923858. 124. Agarwal VR, Bulun SE, Leitch M, Rohrich R, Simpson ER. Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J Clin Endocrinol Metab. 1996 Nov;81(11):3843-9. PubMed PMID: 8923826. 125. Young J, Bulun SE, Agarwal V, Couzinet B, Mendelson CR, Simpson ER, Schaison G. Aromatase expression in a feminizing adrenocortical tumor. J Clin Endocrinol Metab. 1996 Sep;81(9):3173-6. PubMed PMID: 8784064. 126. Rink JD, Simpson ER, Barnard JJ, Bulun SE. Cellular characterization of adipose tissue from various body sites of women. J Clin Endocrinol Metab. 1996 Jul;81(7):2443-7. PubMed PMID: 8675558. 127. Crichton MB, Nichols JE, Zhao Y, Bulun SE, Simpson ER. Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells. Mol Cell Endocrinol. 1996 Apr 19;118(1-2):215-20. Erratum in: Mol Cell Endocrinol 1996 Jul 1;120(2):215. PubMed PMID: 8735608. 128. Bulun SE, Sharda G, Rink J, Sharma S, Simpson ER. Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast. J Clin Endocrinol Metab. 1996 Mar;81(3):1273-7. PubMed PMID: 772611. 129. Bulun SE. Clinical review 78: Aromatase deficiency in women and men: would you have predicted the phenotypes? J Clin Endocrinol Metab. 1996 Mar;81(3):867-71. Review. PubMed PMID: 8772541. 130. Noble LS, Simpson ER, Johns A, Bulun SE. Aromatase expression in endometriosis. J Clin Endocrinol Metab. 1996 Jan;81(1):174-9. PubMed PMID: 8550748. 131. Agarwal VR, Bulun SE, Simpson ER. Quantitative detection of alternatively spliced transcripts of the aromatase cytochrome P450 (CYP19) gene in aromatase-expressing human cells by competitive RT-PCR. Mol Cell Probes. 1995 Dec;9(6):453-64. PubMed PMID: 8808317. 132. Zhao Y, Nichols JE, Bulun SE, Mendelson CR, Simpson ER. Aromatase P450 gene expression in human adipose tissue. Role of a Jak/STAT pathway in regulation of the adipose-specific promoter. J Biol Chem. 1995 Jul 7;270(27):16449-57. PubMed PMID: 7608217. 133. Nichols JE, Bulun SE, Simpson ER. Effects of conditioned medium from different cultured cell types on aromatase expression in adipose stromal cells. J Soc Gynecol Investig. 1995 Jan-Feb;2(1):45-50. PubMed PMID: 9420848. 134. Young S, Gooneratne S, Straus FH 2nd, Zeller WP, Bulun SE, Rosenthal IM. Feminizing Sertoli cell tumors in boys with Peutz-Jeghers syndrome. Am J Surg Pathol. 1995 Jan;19(1):50-8. PubMed PMID: 7802138. 135. Bulun SE, Economos K, Miller D, Simpson ER. CYP19 (aromatase cytochrome P450) gene expression in human malignant endometrial tumors. J Clin Endocrinol Metab. 1994 Dec;79(6):1831-4. PubMed PMID: 7989490. 136. Bulun SE, Simpson ER. Breast cancer and expression of aromatase in breast adipose tissue. Trends Endocrinol Metab. 1994 Apr;5(3):113-20. PubMed PMID: 18407196. 137. Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab. 1994 Mar;78(3):736-43. PubMed PMID: 8126151. 138. Bulun SE, Simpson ER. Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab. 1994 Feb;78(2):428-32. PubMed PMID: 8106632. 139. Bulun SE, Rosenthal IM, Brodie AM, Inkster SE, Zeller WP, DiGeorge AM, Frasier SD, Kilgore MW, Simpson ER. Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads. J Clin Endocrinol Metab. 1994 Feb;78(2):1616-21. PubMed PMID: 8106605.

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140. Bulun SE, Simpson ER. Regulation of aromatase expression in human tissues. Breast Cancer Res Treat. 1994;30(1):19-29. Review. PubMed PMID: 7949202. 141. Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab. 1993 Dec;77(6):1622-8. Erratum in: J Clin Endocrinol Metab 1994 Feb;78(2):494. PubMed PMID: 8117355. 142. Bulun SE, Mahendroo MS, Simpson ER. Polymerase chain reaction amplification fails to detect aromatase cytochrome P450 transcripts in normal human endometrium or decidua. J Clin Endocrinol Metab. 1993 Jun;76(6):1458-63. PubMed PMID: 7684741.

Proceedings of Conferences: 143. Bulun SE, Lin Z, Zhao H, Lu M, Amin S, Reierstad S, Chen D. Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci. 2009 Feb;1155:121-31. Review. PubMed PMID: 19250199. 144. Kim JJ, Sefton EC, Bulun SE. Progesterone receptor action in leiomyoma and endometrial cancer. Prog Mol Biol Transl Sci. 2009;87:53-85. Epub 2009 Oct 7. Review. PubMed PMID: 20374701. 145. Bulun SE, Simpson ER. Aromatase expression in women's cancers. Adv Exp Med Biol. 2008;630:112-32. Review. PubMed PMID: 18637488. 146. Anderson H, Bulun SE, Smith I, Dowsett M: Predictors of response to aromatase inhibitors. J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):49-54. Epub 2007 May 24. PMID: 17604158. 147. Bulun SE, Chen D, Lu M, Zhao H, Cheng Y, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Su E, Marsh E, Hakim A, Yin P, Ishikawa H, Amin S, Imir G, Gurates B, Attar E, Reierstad S, Innes J, Lin Z: Aromatase excess in cancers of breast, endometrium and ovary. J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):81-96. Epub 2007 May 24. PMID: 17590327. 148. Marsh EE, Bulun SE. Steroid hormones and leiomyomas. Obstet Gynecol Clin North Am. 2006 Mar;33(1):59-67. Review. PubMed PMID: 16504806. 149. Attar, Bulun SE. Aromatase Inhibitors: The next wave in treatment of endometriosis? Contemporary Obstetrics and Gynecology. 2006, Nov 1. 150. Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, Lin Z. Aromatase in endometriosis and uterine leiomyomata. J Steroid Biochem Mol Biol. 2005 May;95(1-5):57-62. Review. PubMed PMID: 16024248. 151. Bulun SE: Aromatase: update and new roles in reproductive disease. Semin Reprod Med. 2004. 22:3. 152. Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol. 2003 Sep;86(3- 5):219-24. Review. PubMed PMID: 14623514. 153. Bulun SE, Gurates B, Fang Z, Tamura M, Sebastian S, Zhou J, Amin S, Yang S. Mechanisms of excessive estrogen formation in endometriosis. J Reprod Immunol. 2002 May-Jun;55(1-2):21-33. Review. PubMed PMID: 12062819. 154. Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Sebastian S. Estrogen production and metabolism in endometriosis. Ann N Y Acad Sci. 2002 Mar;955:75-85; discussion 86-8, 396-406. Review. PubMed PMID: 11949967. 155. Fazleabas A, A Brudney, B Gurates, D Chai and Bulun SE: A Modified Baboon Model for Endometriosis. Endometriosis. Ann N Y Acad Sci. 2002 Mar;955:308-17; discussion 340-2, 396-406. Review. PMID: 11949957. 156. Takayama K, Bulun SE. [Endometriosis and aromatase inhibitor]. Nihon Rinsho. 2001 Jan;59 Suppl 1:157-60. Review. Japanese. PubMed PMID: 11235156. 157. Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Zhou J, Sebastian S. Role of aromatase in endometrial disease. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):19-25. Review. PubMed PMID: 11850203. 158. Simpson ER, C Clyne, C Speed, G Rubin, and Bulun SE: Tissue-specific estrogen biosynthesis and metabolism. Annals of the New York Academy of Sciences. 949:58-67 (2001). 159. Bulun SE, Noble LS, Takayama K, Michael MD, Agarwal V, Fisher C, Zhao Y, Hinshelwood MM, Ito Y, Simpson ER. Endocrine disorders associated with inappropriately high aromatase expression. J Steroid Biochem Mol Biol. 1997 Apr;61(3-6):133-9. Review. PubMed PMID: 9365182. 160. Simpson ER, Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood MM, Graham-Lorence S, Sun T, Fisher

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CR, Qin K, Mendelson CR. Aromatase expression in health and disease. Recent Prog Horm Res. 1997;52:185-213; discussion 213-4. Review. PubMed PMID: 9238853. 161. Simpson ER, Michael MD, Agarwal VR, Hinshelwood MM, Bulun SE, Zhao Y. Cytochromes P450 11: expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usage. FASEB J. 1997 Jan;11(1):29-36. Review. PubMed PMID: 9034163. 162. Simpson ER, Bulun SE, Nichols JE, Zhao Y. Estrogen biosynthesis in adipose tissue: regulation by paracrine and autocrine mechanisms. J Endocrinol. 1996 Sep;150 Suppl:S51-7. PubMed PMID: 8943787. 163. Simpson ER, MS Mahendroo, MW Kilgore, GD Means, Bulun SE, MM Hinshelwood, and CR Mendelson: The aromatase reaction. Adv Mol Cell Biol. 1996. 14:225-244. 164. Bulun SE, Mahendroo MS, Simpson ER. Aromatase gene expression in adipose tissue: relationship to breast cancer. J Steroid Biochem Mol Biol. 1994 Jun;49(4-6):319-26. Review. PubMed PMID: 8043495

Chapters and Book Reviews: 1. Bulun SE: The Physiology and Pathology of the Female Reproductive Axis. Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. In: Williams Textbook of Endocrinology, 12th ed, WB Saunders Company, Philadelphia, (2012). 2. Bulun SE and EY Adashi: The Physiology and Pathology of the Female Reproductive Axis. Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. In: Williams Textbook of Endocrinology, 10th and 11th eds, WB Saunders Company, Philadelphia, (2008). 3. Bulun SE and EY Adashi: The Physiology and Pathology of the Female Reproductive Axis. Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. In: Williams Textbook of Endocrinology, 10th and 11th eds, WB Saunders Company, Philadelphia, (2003). 4. Bulun SE and ER Simpson: Aromatase Expression in Women’s Cancers. Berstein L , Santen RJ, editors. In: Innovative Endocrinology in Cancer, Landes Bioscience / Eurekah.com: Austin, TX (2007). 5. Attar E and Bulun SE: Endometriosis. Giudice L, Fazleabas A, editors. London, UK: Informa healthcare. In: The Endometrium: Molecular, Cellular and Clinical Perspectives, 2nd Ed., Ch 45 (2007). 6. Bulun SE and Marsh EE: Hormone Action. Van Voorhis BJ, and LC Layman, editors. American College of Obstetricans and Gynecologists, publisher. In: Precis An Update in Obstetrics and Gynecology: Reproductive Endocrinology 3rd Edition, 3-30 (2007). 7. Bulun SE, B Gurates, Z Fang , T Mitsutoshi, D Langoi, G Imir, S Amin, S Deb, and S Yang: Pathophysiology Underlying Treatment of Endometriosis with Aromatase Inhibitors. Tulandi T and Redwine D, editors. In: Endometriosis: Advances and Controversies, 189-202 (2003). 8. Nelson LR and Bulun SE: Aromatase: Glandular and Extraglandular activity. In: Reproductive Medicine: Molecular Cellular and Genetic Fundamentals. B.C.J.M. Fauser (Ed.), Parthenon Publishing, 267-278 (2003). 9. Bulun SE and ER Simpson: Aromatase deficiency. Martini L, Chrousos GP, editors. In: Hormone Resistance. New York: Raven Press. 467-75 (2002). 10. Bulun SE and ER Simpson: Estrogen action, breast. Knobil E, Neill JD, editors. In: Encyclopedia of Reproduction. San Diego, CA: Academic Press, Inc. 2:71-79 (1999). 11. Bulun SE, ER Simpson and CR Mendelson: The molecular basis of hormone action. Carr BR, Blackwell RE, editors. In: Textbook of Reproductive Medicine. 2nd ed. Norwalk, CT: Appleton&Lange. 7:137-156 (1998). 12. Simpson ER, MD Michael, VR Agarwal, MM Hinshelwood, Bulun SE, and Y Zhao: Tissue-specific expression of the CYP19 (aromatase) gene. Leroith, D, editor. In: Advances in Molecular and Cellular Endocrinology. JAI Press Inc. 2:99-120 (1998). 13. Zeitoun K and Bulun SE: Review of “Hormones and Cancer”. Vedeckis WV, editor. Boston, MA: Birkhauser In: Trends in Endocrinology and Metabolism. 8:290-291 (1997). 14. Bulun SE, LS Noble, K Takayama, MD Michael, C Fisher, Y Zhao, MM Hinshelwood, Y Ito, VR Agarwal and ER Simpson: The human aromatase enzyme: from gene to clinic. In: FSH Action and Intraovarian Regulation. Fauser BJCM, editor Carnforth, UK: Parthenon Publishing Group Limited. 6:233-246 (1997). 15. Bulun SE and MS Piver: Review of “Benign Diseases of the Vulva and Vagina”, 3rd ed. Kaufman RH, Friedrich EG, editors. New York, NY: Springer-Verlag, Adolescent and Pediatric Gynecology. 3:119-20 (1990).

Abstracts (National Meetings):

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1. Pavone ME, Malpani S, Dyson M, Monsivais D, Mittal N, Bulun SE. Differences in Retinoid Uptake and Metabolism Alters Paracrine Signaling in Endometriosis. Oral presentation, ASRM 2013. 2. Dyson M, Roqueiro D, Monsivais D, Ercan CM, Jafari, N, Pavone, ME, Bulun SE. Interrogating DNA methylation difference in endometriosis identifies a GATA switch. LLES-9th Annual Lewis Landsberg Research Day. April 4th, 2013. 3. Monsivias D, Dyson M, Navarro A, Ercan CM, Pavone ME, Su E, Bulun SE. Characterizing ERβ regulated genes in Endometriosis. Society for the Study of Reproduction. July 24th, 2013, Montreal, Canada. 4. Su EJ, Xin H, Monsivias D, Bulun SE. Estrogen receptor-beta mediates impaired fetoplacental angiogenesis in fetal growth restriction. Society of Gynecologic Investigation 2013 Annual Meeting. Orlando, FL. (Poster presentation) 5. Hong Zhao, Elizabeth K. Pearson, Robert T. Chatterton, Zhenghong Yu2, David C. Brooks, Takeshi Kurita, Diana Berger, Francesco J. DeMayo and Bulun SE. A Novel Role of Estrogen/Kisspeptin in the Development of Inguinal Hernia, The American Society for Clinical Investigation/Association of American of Physicians Joint Meeting, Chicago, Illinois, 2013. (Presentation TBD) 6. M. Ono, P. Yin, A. Navarro, J. Coon, D. Brooks, S. Malpani, J. Ma, W. Qiang, V. Serna, S. Druschitz, T. Kurita, C. Gottardi, Bulun SE. Paracrine Wnt/β-Catenin Signaling Between Stem Cells and Main Population in Uterine Fibroid Cell Growth. The American Society for Clinical Investigation/Association of American of Physicians Joint Meeting, Chicago, Illinois, 2013. (Poster Presentation) 7. Masanori Ono, Ping Yin, Antonia Navarro, John Coon V, David Chris Brooks, Saurabh Malpani, Jiajia Ma, Navdha Mittal, Wenan Qiang, Vanida Ann Serna, Stacy Druschitz, Takeshi Kurita, Cara Gottardi, Bulun SE. Wnt/β-Catenin: Paracrine Signaling Between Stem Cells and Main Population in Uterine Fibroid Cell Growth. Society for Gynecologic Investigation, 60th Annual Scientific Meeting, Orlando, Florida, 2013. (Oral Presentation) 8. Hong Zhao, John S. Coon V, Robert T Chatterton, Dolores Huberts, David Christopher Brooks, Francesco J. DeMayo and Bulun SE. Estrogen accelerates the development of estrogen receptor-negative breast cancer, American Association for Cancer Research, Washington, DC, 2013. (Poster Presentation). 9. Su EJ, Xin H, Monsivais D, Bulun SE. Estrogen receptor-beta (ESR2) inhibits induction of hypoxia-mediated genes critical for normal fetoplacental vascular angiogenesis. Society for Maternal-Fetal Medicine 33rd Annual Meeting. San Francisco, California, 2013. (Poster Presentation) 10. Su EJ, Xin H, Jie C, Jafari N, Dyson M, Bulun SE. Fetoplacental endothelium demonstrate unique responses to physiologic hypoxemia. Society for Maternal-Fetal Medicine 33rd Annual Meeting. San Francisco, CA, 2013. (Poster Presentation) 11. Masanori Ono, Wenan Qiang, Vanida Ann Serna, John V Coon, Antonia Navarro, Ping Yin, Toshiyuki Kakinuma, Stacy Druschitz, Kenji Unno, Takeshi Kurita, Bulun SE. Role of Stem Cells in Human Uterine Leiomyoma Growth, Society for Gynecologic Investigation, San Diego, California, 2012. (Oral Presentation) 12. Matthew T. Dyson, Toshiyuki Kakinuma, Diana Monsivais, Bulun SE. Interrogating Altered DNA Methylation in Human Endometriotic Stromal Cells. Society for the Study of Reproduction, 45th Annual Meeting, State College, Pennsylvania, 2012. (Poster Presentation) 13. M.E. Pavone, S. Malpani, M. Dyson, D. Monsivais, Bulun SE. Fenretinide as a novel treatment for endometriosis. Oral presentation, American Society for Reproductive Medicine, San Diego, California, 2012. (Oral Presentation) 14. M.E. Pavone, S. Malpani, M. Dyson, D. Monsivais, T. Kakinuma, Bulun SE. Differences in retinoid uptake and metabolism causes altered paracrine signaling in endometriosis. American Society for Reproductive Medicine, San Diego, California, 2012. (Oral Presentation). 15. Mary Ellen Pavone, Matthew Dyson, Saurabh Malpani, Toshiyuki Kakinuma, and Bulun SE. Decidualization Alters Vitamin A Signaling in Endometrium, Society for Gynecologic Investigation, San Diego, California, 2012. (Poster Presentation). 16. A. Navarro, P. Ying, D. Monsivais, M. Ono, Bulun SE. The Role of Matrix Metalloproteinase-11 (MMP11) in Human Uterine Leiomyomas. Society for the Study of Reproduction, State College, Pennsylvania, 2012. (Poster Presentation) 17. Dyson M, Pavone ME, Kakinuma T, Bulun SE. Increased RAR-related orphan receptor beta expression accompanies altered retinoid metabolism during endometrial stromal cell decidualization. Society for the Study of Reproduction. 44th Annual Meeting, Portland, Oregon, 2011. 18. Pavone ME, Cheng YH, Fazlebas, A, Bulun SE: Retinoic acid action is deficient in endometrium in a baboon

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endometriosis model. Society for Gynecologic Investigation 57th Annual Meeting, Miami, FL 2011. (Oral Presentation). 19. Su E, Abdallah N, Ernst L, Yin P, Bulun SE. Fetoplacental endothelia cell expression of 17-beta hydroxysteroid dehydrogenase type 2 mediates cyclooxygenase expression. Society for Gynecologic Investigation 57th Annual Meeting, Miami, FL 2011. 20. Ishikawa H, Ishi K, Serna VA, Kakzu R, Bulun SE, Kurita T. Progesterone is essential for maintenance and growth of uterine leiomyoma. American Society for Reproductive Medicine Denver, Colorado, 2010. (Oral Presentation). 21. Chen D, Reierstad S, Coon J and Bulun SE: [P3-53] JunB and JunD Mediate PGE2 Activation of Breast Cancer- Associated Aromatase Promoters in Human Breast Adipose Fibroblasts. The Endocrine Society, 92nd Annual Meeting, San Diego, California, 2010 (Poster Presentation). 22. Moy I, Reierstad S, Huang S and Bulun SE: Molecular predictors of response to aromatase inhibitors in breast cancer. The Endocrine Society, 92nd Annual Meeting, San Diego, California, 2010 (Poster Presentation). 23. Pavone ME, Pearson E, Cheng YH, Bulun SE: Endometriotic Stromal Cells Express a Molecular Pattern Consistent with Decreased Retinoid Uptake, Metabolism and Action. American Society for Reproductive Medicine, Atlanta, Georgia, 2009. (Oral Presentation; ASRM “in-training” award). 24. Yin P, Coon J, Pearson E, Su E, Bulun SE. RU486 Up-regulated LAT1 inhibits uterine fibroid growth. Society for Gynecologic Investigation 57th Annual Meeting, Miami, FL 2010. 25. Luo X, Yin P, Coon J, Cheng, YH, Bulun SE. The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells. Society for Gynecologic Investigation 57th Annual Meeting, Miami, FL 2010. 26. Pavone ME, Pearson E, Cheng YH, Bulun SE: Progesterone Receptor is a Necessary but Not Sufficient Regulator of Genes Involved in the Retinoic Acid Signaling Pathway in Endometrium and Endometriosis. The Endocrine Society, Washington, DC, 2009. (Poster Presentation; Presidential Poster Competition Nominee). 27. Pavone ME, Reierstad S, Pearson E, Cheng YH, Bulun SE: Endometriosis Expresses a Molecular Pattern Suggesting an Alteration in Retinoid Uptake and Metabolism. Pacific Coast Reproductive Society, 2009. (Oral Presentation; Outstanding Paper Award). 28. Pavone ME, Reierstad S, Pearson EK, Cheng YH and Bulun SE: Resistance to apoptosis in endometriosis may be caused by a decreased CRABPII/FABP5 Ratio. Society for Gynecologic Investigation, 56th Annual Meeting, Glasgow, Scotland, 2009 (Poster Presentation). 29. Pavone ME, Bulun SE, Sun H, Reierstad SS, Innes J, Cheng YH: Progesterone-Dependent Induction of STRA6 regulates Retinoic Acid action in the Endometrium. American Society for Reproductive Medicine, San Francisco, California, 2008. (Poster Presentation). 30. Pavone ME, Bulun SE, Reierstad S, Innes J, Milad MP, Cheng YH: STRA6 is Expressed and Induced by Progesterone in the Endometrium and is Absent in Endometriosis. Society for Gynecologic Investigation, San Diego, California, 2008. (Poster Presentation). 31. Chen D, Reierstad S and Bulun SE: Role of ATF2 and c-Jun in PGE2 regulation of aromatase expression in human breast adipose fibroblasts. The Endocrine Society, 90th Annual Meeting, San Francisco, California, 2008 (Poster Presentation). 32. Marsh EE, Pearson EK, Yin P; Ishikawa H, Kim JJ and Bulun SE: Expression of steroidogenic acute regulatory (StAR) protein, CYP11A1 and CYP17A1 mRNA in human normal myometrium and leiomyoma tissue. The Endocrine Society, 90th Annual Meeting, San Francisco, California, 2008 (Poster Presentation). 33. Ishikawa H, Yin P, Marsh EE and Bulun SE: SOX8 is a novel target gene of progesterone in uterine leiomyoma. The Endocrine Society, 90th Annual Meeting, San Francisco, California, 2008 (Poster Presentation). 34. Lin Z, Yin P, Reierstad S, O’Halloran M, Chen D and Bulun SE: Modulation of estrogen receptor α function and stability by Adora1 in MCF-7 human breast cancer cell. The Endocrine Society, 90th Annual Meeting, San Francisco, California, 2008 (Poster Presentation). 35. Cheng YH, Utsunomiya H and Bulun SE: Identification of the retinoic acid (RA) target genes in human endometrial epithelial cells. The Endocrine Society, 90th Annual Meeting, San Francisco, California, 2008 (Poster Presentation). 36. Su EJ, Lin Z, Yin P, Reierstad S, Innes J and Bulun SE: Estradiol mediates genes involved in prostanoid production in placental villous endothelial cells. Society for Gynecological Investigation, 55th Annual Meeting, San Diego, California, 2008 (Poster Presentation). 37. Pavone ME, Bulun SE, Reierstad SS, Innes J, Milad MP and YH Cheng: STRA6 is expressed and induced by progesterone in the endometrium and is absent in endometriosis. Society for Gynecological Investigation, 55th Annual Meeting, San Diego, California, 2008 (Poster Presentation).

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38. Zhao H, Innes J, Reierstad S, Yilmaz MB and Bulun SE: A novel promoter controls Cyp19a1 gene expression in mouse adipose tissue. Society for Gynecological Investigation, 55th Annual Meeting, San Diego, California, 2008 (Oral Presentation). 39. Yin P, Lin Z, Reierstad S, Cheng YH, Marsh EE, Ishikawa H, Innes J, Kim JJ and Bulun SE: Chromatin immunoprecipitation cloning identifies KLF11 as a novel progesterone receptor target gene that regulates proliferation in uterine leiomyoma. Society for Gynecological Investigation, 55th Annual Meeting, San Diego, California, 2008 (Oral Presentation). 40. Ishikawa H, Fencki IV, Marsh EE, Yin P, Cheng YH, Lin Z and Bulun SE: CCAAT enhancer binding protein beta (C/EBPβ) regulates cAMP dependent aromatase expression via novel and multiple cis-acting element in uterine leiomyoma. Society for Gynecological Investigation, 55th Annual Meeting, San Diego, California, 2008 (Oral Presentation). 41. Ishikawa H, I Fencki, EE Marsh, P Yin, D Chakravarti and Bulun SE: CCAAT Enhancer Binding Protein Beta (C/EBPb) Regulates Aromatase P450 Expression via New Cis – acting Element in Uterine Leiomyoma Cells. American Society for Reproductive Medicine, 63rd Annual Meeting, 2007 (Oral Presentation). 42. Marsh EE, Z Lin, P Yin, E Confino, M Milad, and Bulun SE. Leptin Increases VEGF and VEGF-Receptor Expression in Human Uterine Leiomyoma Cells In Vitro. American Society for Reproductive Medicine, 63rd Annual Meeting, 2007 (Oral Presentation). 43. Trukhacheva E, Lin Z, Reierstad S, Innes J, Marsh EE, Xue Q, Cheng YH and Bulun SE: ER-beta regulates ER- alpha expression and response to estradiol via specific promoters in endometrium and endometriosis. American Society for Reproductive Medicine, 63rd Annual Meeting, 2007 (Oral Presentation). 44. Marsh EE, H Ishikawa, P Yin and Bulun SE. The Role and Regulation of Aromatase in Human Uterine Leiomyoma. NICHD Uterine Fibroid Research Update Workshop. Bethesda, MD September, 2007 (Oral Presentation). 45. Wang Y, E Marsh, Bulun SE and E Xu: Stem cell markers in mouse and human uterine myometrium and leiomyoma. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 46. Xue Q, Z Lin, P Yin, M Milad , H Utsunomiya, E Confino, S Reierstad, E Marsh, and Bulun SE: Methylation of SF-1 (steroidogenic factor-1) promoter regulates its expression in endometrial vs. endometriotic stromal cells. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 47. Chen D, S Reierstad, Z Lin, C Brooks, and Bulun SE: PGE2 Induces Breast Cancer-related Aromatase Promoters via Activation of p38 and JNK in Adipose Fibroblasts. The Endocrine Society, 89th Annual Meeting, Toronto, Canada, June 2007 (Poster Presentation).

48. Yin P, Z Lin, EE Marsh, YH Cheng, H Ishikawa, Q Xue, S Reierstad, J Innes, JJ Kim, E Xu and Bulun SE: Identification of novel progesterone receptor target genes in uterine leiomyoma. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 49. Cheng YH, P Yin, B Yilmaz, P Ken, M Dawson and Bulun SE: Transcriptional regulation of 17beta-hydroxysteroid dehydrogenase type 2 (HSD17B2) gene by retinoic acid is via RA receptors (RAR/RXR) interaction with SP1 and SP3 in the human endometrium. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 50. Marsh EE, Z Lin, P Yin, E Xu, D Chakravarti and Bulun SE: MicroRNA species are differentially expressed in human uterine leiomyoma versus adjacent normal myometrium. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 51. Trukhacheva E, Z Lin, S Reierstad, J Innes, E Marsh, Q Xue, Y Cheng and Bulun SE: Estradiol regulates ESR1 (ER-α) gene expression via alternative promoters in endometrium and endometriosis. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 52. Lu M and Bulun SE: BRCA1 modulates aromatase activity via interacting with its promoter I.3/ II region in breast adipose fibroblasts. The Endocrine Society, 89th Annual Meeting, Toronto, Canada, June 2007 (Poster Presentation). 53. Ishikawa H, V Fencki, E Marsh, P Yin, D Chakravarti and Bulun SE: CAATT/enhancer binding proteins binding element and cAMP response element play crucial role for aromatase expression in uterine fibroid. The Endocrine Society, 89th Annual Meeting, 2007 (Poster Presentation). 54. Hakim A, Z Lin, S Reierstad, G Rodriguez, P Yin, J Lurain, J Schink and Bulun SE: Interferon Regulatory Factor-β Mediates Progesterone Action In Ovarian Cancer. Society for Gynecologic Investigation, 54th annual meeting, Reno, Nevada, 2007 (Poster Presentation). 55. Xue Q, Z Lin, P Yin, E Marsh, S Reierstad and Bulun SE: Differential expression of ERβ in endometrial and endometriotic stromal cells: regulation by methylation. Society for Gynecologic Investigation, 54th annual meeting,

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Reno, Nevada, 2007 (Oral Presentation). 56. Yin P, Z Lin, YH Cheng, EE Marsh, H Utsunomiya, H Ishikawa, S Reierstad, JJ Kim, E Xu, and Bulun SE: A sequence in the 5’ flanking region on the human Bcl-2 gene confers progestin responsiveness in uterine leiomyoma cells in vitro. Society for Gynecologic Investigation, 54th annual meeting, Reno, Nevada, 2007 (Poster Presentation). 57. Ishikawa H, V Fenkci, EE Marsh, P Yin, D Chakravarti and Bulun SE: Aromatase expression in uterine fibroid cells is regulated by promoter elements that bind CAATT/enhancer binding proteins (C/EBPs). Society for Gynecologic Investigation, 54th annual meeting, Reno, Nevada, 2007 (Poster Presentation). 58. Hoekstra A, EC Ward , Z Lu, JL Hardt, E Marsh, P Yin, Bulun SE and JJ Kim: The forkhead family of transcription factors are differentially expressed and regulated in leiomyoma and myometrial cells. Society of Gynecological Investigation, 54th Annual Meeting, Reno, Nevada, 2007 (Oral Presentation). 59. Marsh E, Z lin, M Demura, P Yin, E Xu, J.J Kim and Bulun SE: Leptin increases aromatase expression in human leiomyoma cells primarily via the Jak-Stat pathway and aromatase promoter I.4 region. Society of Gynecological Investigation, 54th Annual Meeting, Reno, Nevada, 2007 (Oral Presentation). 60. Amin SA, Z Lin, J Innes, JJ Kim, and Bulun SE: Malignant epithelial derived IL-1beta in paracrine interaction with benign stromal fibroblasts. Sigma Xi Science Graduate Student Research Forum, University of Illinois at Chicago, 2006 (Poster Presentation; 3rd place award winner). 61. Amin SA, Z Lin, J Innes, JJ Kim, and Bulun SE: Malignant epithelial-derived IL-1beta exerts paracrine effects on benign mammary fibroblasts that favor estradiol production. Indian-American Medical Association, Annual Research Forum, Chicago, 2006 (Poster Presentation; 1st place award winner). 62. Lu M, D Chen, Z Lin, S Reierstad, A Trauernicht, T Boyer and Bulun SE: BRCA1 negatively regulates the cancer- associated aromatase promoters I.3 and II in breast adipose fibroblasts and malignant epithelial cells. VIII International Aromatase Conference, Baltimore, Maryland, 2006 (Poster Presentation). 63. Lin Z, S Reierstad, C Huang and Bulun SE: Novel estradiol target genes uncovered by genome-wide mapping of estrogen receptor-a binding sites. VIII International Aromatase Conference, Baltimore, Maryland, 2006 (Poster Presentation). 64. Marsh E, Z Lin, P Yin, E Confino and Bulun SE: Increased aromatase mRNA expression and cell proliferation in human leiomyoma cells with leptin treatment. VIII International Aromatase Conference, Baltimore, Maryland, 2006 (Poster Presentation). 65. Demura M and Bulun SE: A novel mechanism of gain-of-function mutation of CYP19 gene in familial aromatase excess syndrome. ASCI/AAP Joint Meeting, Chicago, IL, 2006 (poster presentation). 66. Bulun SE, M Demura, R Martin, S Sebastian, K Takayama, WT Hsu, R Schultz, K Neely, M Bryant , B Mendonca, K Hanaki, S Kanzaki, D Rhoads, M Misra, S Reierstad, J Innes and M Shozu: Heterozygous rearrangements in chromosome 15q21 form cryptic promoters that overexpress aromatase and cause estrogen excess in both sexes. Research Society of Growth Disturbance in Children, 20th Annual Meeting, Japan, 2006 (Oral Presentation). 67. Demura M and Bulun SE: Methylation status of CpG dinucleotides within the CYP19 gene promoter I.3/II region regulates aromatase expression in human fibroblasts. San Antonio Breast Cancer Symposium, 29th Annual Meeting San Antonio, Texas, 2006 (poster presentation). 68. Lin Z, S. Reierstad, H. Cotterill, A.W. Rademaker, S.A. Khan, B. Hayes, R.A Hern, I. Smith, J. Innes, M. Dowsett and Bulun SE: Messenger RNA levels of estrogen-related genes in malignant breast tumor tissue predict responsiveness to aromatase inhibitors. San Antonio Breast Cancer Symposium, 29th Annual Meeting, San Antonio, Texas, 2006 (oral presentation). 69. Marsh E, Z Lin, P Yin and Bulun SE: Role of microRNAs in human uterine leiomyoma pathogenesis and growth. American Society for Reproductive Medicine, 62nd Annual Meeting, New Orleans, Louisiana, 2006 (Poster Presentation). 70. Attar E, V Fenkci, MB Yilmaz , M Demura, H Utsunomiya and Bulun SE: Taurine transporter (TauT), a novel target of sodium butyrate in suppression of aromatase expression in stromal cells derived from endometriosis. American Society for Reproductive Medicine, 62nd Annual Meeting, New Orleans, Louisiana, 2006 (Oral Presentation). 71. Xue Q, Z Lin, H Utsunomiya, M Demura, M Milad and Bulun SE: Differential expression of SF-1 (steroidogenic factor-1) in endometrial and endometriotic stromal cells: regulation of methylation. American Society for Reproductive Medicine, 62nd Annual Meeting, New Orleans, Louisiana, 2006 (Oral Presentation & In Training Award). 72. Lin Z, S Reierstad, CC Huang and Bulun SE: Novel estradiol target genese uncovered by genome-wide mapping of estrogen receptor-α binding sites. VIII International Aromatase Conference, Baltimore, Maryland, 2006 (Poster Presentation).

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73. Demura M and Bulun SE: Heterozygous rearrangements in chromosome 15q21 from cryptic promoters that induce aromatase overexpression. VIII International Aromatase Conference, Baltimore, Maryland, 2006 (poster presentation). 74. Marsh E, P Yin, S Reierstad and Bulun SE: In vivo and in vitro expression of leptin and leptin receptor in human myometrium and leiomyoma. The Endocrine Society, 88th Annual Meeting, Boston, Massachusetts, 2006 (Poster Presentation). 75. Cheng Y, M Dawson and Bulun SE: Retinoids Regulate 17β-Hydroxysteroid Dehydrogenase Type 2 Gene in the Human Endometrium. The Endocrine Society, 88th Annual Meeting, Boston, Massachusetts, 2006 (Poster Presentation). 76. Demura M, D Rhoads, M Misra, S Reierstad, J Innes and Bulun SE: A novel heterozygous inversion mutation causes the talin 2 (TLN2) gene promoter region with novel untranslated First 2 exons to lie adjacent to the CYP19 gene at a 185-kb from a 11.2-Mb distance, leading to aromatase excess syndrome in a sporadic male case. The Endocrine Society, 88th Annual Meeting, Boston, Massachusetts, 2006 (Poster Presentation). 77. Lin Z, S Reierstad, S Huang and Bulun SE: Novel binding patterns of estrogen receptor-α to its target genes in breast cancer. The Endocrine Society, 88th Annual Meeting, Boston, Massachusetts, 2006 (Oral Presentation). 78. Chen D, Z Lin and Bulun SE: Activation of p38 and JNK is Necessary for cAMP/Phorbol Ester-Stimulated Aromatase Expression in Human Breast Adipose Fibroblasts. The Endocrine Society, 88th Annual Meeting, Boston, Massachusetts, 2006 (Poster Presentation). 79. Yin P, Z Lin, S Reierstad, E Marsh, H Utsunomiya, S Thung and Bulun SE: The effects of progesterone on cell survival and Bcl-2 mRNA levels in leiomyoma smooth muscle cells. Society of Gynecological Investigation, 53rd Annual Meeting, Toronto, Canada, 2006 (Poster Presentation). 80. Thung S, Z Lin, Y Chen, H Utsunomiya, P Yin and Bulun SE: 17β-hydroxysteroid dehydrogenase expression in response to progesterone in endometrial biopsy and Ishikawa cell culture. Society of Gynecological Investigation, 53rd Annual Meeting, Toronto, Canada, 2006 (Poster Presentation). 81. Su E, Y Chen, S Reierstad, J Kim, J Innes and Bulun SE: 17β-hydroxysteroid dehydrogenase type 2 expression in human placental microvascular endothelial cells. Society of Gynecological Investigation, 53rd Annual Meeting, Toronto, Canada, 2006 (Poster Presentation). 82. Attar E, B Yilmaz, J Innes, H Utsinomiya, M Demura and Bulun SE: Sodium butyrate is a tissue specific inhibitor of aromatase expression in endometriosis. Society of Gynecological Investigation, 53rd Annual Meeting, Toronto, Canada, 2006 (Oral Presentation). 83. Cheng Y, AG Imir, SF Thung and Bulun SE: A Stromal Defect In Endometriosis is Responsible for Lack of Induction of Epithelial Sp-1 And 17β-Hydroxysteroid-Dehydrogenase by Progesterone. American Society for Reproductive Medicine, 61st Annual Meeting, Montreal, Quebec, 2005 (Poster presentation). 84. Martin R, M Nishi, M Demura, C Lin, B Mendonca, and Bulun SE: Rearrangement between CYP19 and MAPK6 genes as cause of aromatase excess syndrome in a Brazilian family. The Endocrine Society, 87th Annual Meeting, San Diego, CA, 2005 (Oral Presentation). 85. Demura M, S Sabastian, M Shozu, W Hsu, K Neely, M Bryant and Bulun SE: Loop formation-induced inversion causes a gain-of-function mutation in estrogen excess syndrome with the hybrid FLJ14957/CTYP19 gene. The Endocrine Society, 87th Annual Meeting, San Diego, CA, 2005 (Oral Presentation). 86. EE Marsh, S Reierstad, P Yin and Bulun SE: Leptin induces cell proliferation and increased aromatase expression in human leiomyoma cells in vitro. The Endocrine Society, 87th Annual Meeting, San Diego, CA, 2005 (Poster Presentation). 87. Demura M, K Hanaki, S Kanzaki and Bulun SE: Aromatase excess syndrome in a Japanese kindred caused by novel deletion mutation. The Endocrine Society, 87th Annual Meeting, San Diego, CA, 2005 (Poster Presentation). 88. Demura M, S Sebastian, Z Lin, J Wyk, MI New, MO Thorner, EP Smith and Bulun SE: Genetically heterozygous abnormalities of CYP19 promoters in 4 unrelated patients with aromatase excess syndrome: aberrant promoter utilizations and transcription start site switch of promoter I.4. The Endocrine Society, 87th Annual Meeting San Diego, CA, 2005 (Poster Presentation). 89. Amin S, Lin Z, Innes J and Bulun SE: The role of IL-1beta in regulation of adipogenesis, proliferation, and prostaglandin E2 production in normal stromal fibroblasts in breast cancer.American Association for Cancer Research, Annual Meeting, Anaheim, California, Volume 46, 2005 (Poster Presentation). 90. Utsunomiya H, Z Lin, S Thung, G Imir, J Kim and Bulun SE: Determination of the cis-acting in SF-1 promoter that are responsible for aberrant SF-1 expression in endometriotic stromal cells. Society of Gynecological Investigation,

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52nd Annual Meeting, Los Angeles, California 2005 (Poster Presentation). 91. Cheng Y, S Yang, A Imir, Z Fang, S Thung and Bulun SE: Defect of stroma-epithelial interaction in endometriosis is responsible for lack of induction of 17β-hydroxysteroid dehydrogenase (HSD) type 2 progesterone. Society of Gynecological Investigation, 52nd Annual Meeting, Los Angeles, California 2005 (Poster Presentation). 92. Motaghedi R, G Solomon, J Wilson, M Levine, Bulun SE, Korach K, and MI New: Precocious gonadotropin independent puberty with the absence of sex hormones. The Endocrine Society, 86th Annual Meeting, New Orleans, Louisana, 2004 (Poster Presentation). 93. Deb S, S Amin and Bulun SE: Estrogen regulates TNF action on breast adipocyte differentiation. The Endocrine Society, 86th Annual Meeting, New Orleans, Louisana, 2004 (Poster Presentation). 94. Fang Z, S Yang and Bulun SE: Transcription factors SF-1 and WT-1 regulate the steriodogenic acute regulatory protein (StAR) in endometriotic and endometrial stromal cells in response to PGE. Journal of the Society for Gynecological Investigation, 51st Annual meeting, Houston Texas, 2004 (Poster Presentation). 95. Fang Z, S Yang, G Imir and Bulun SE: In Vivo and In Vitro expression of steriodogenic genes and transcription factors in endometriosis. Journal of the Society for Gynecological Investigation, 51st Annual meeting, Houston Texas, 2004 (Poster Presentation). 96. Amin S, S Deb, Z Lin, S Edassery, P Larson, Z Arbieva, and Bulun SE: Gene expression profile of benign fibroblasts in breast cancer in relation to epithelial-stromal interactions. American Association for Cancer Research, ACCR Workshop, Orlando, Flordia, 2004 (Poster Presentation). 97. Bulun SE, L Amsterdam, S Jobanputra, W Gentry and SD Rubin: Treatment of endometriosis-related pain with a combination of an aromatase inhibitor (anastrozole) plus a combination oral contraceptive: a novel approach. The Endocrine Society, 85th Annual Meeting, Philadelphia, PA. 2003 (Poster presentation). 98. Yang S, Z Fang, T Suzuki, H Sasano and Bulun SE: Early growth response-1 (Egr-1) is selectively upregulated in epithelial cells of endometriosis: a mechanism for 17b -hydroxysteroid dehydrogenase (HSD)-2 deficiency in endometriosis. The Society for Gynecologic Investigation, 50th Annual Meeting, Washington, D.C., 2003 (Oral presentation). 99. Fang Z, S Yang, B Gurates and Bulun SE: Intact Estrogen Receptor-a is Essential for the Proliferative Effect of Estradiol in Ectopic Uterine Tissue in a Genetically Engineered Mouse Model of Endometriosis. The Society for Gynecologic Investigation, 50th Annual Meeting, Washington, D.C., 2003 (Oral presentation). 100. Fang Z, S Yang, M Tamura, B Gurates and Bulun SE: Intact progesterone receptors are essential to counteract the proliferative effect of estrogen in a transgenic mouse model of endometriosis. American Society for Reproductive Medicine, 58th Annual Meeting, Seattle, WA, 2002 (Oral presentation). 101. Gurates B, S Sebastian, S Yang, M Tamura, Z Fang and Bulun SE: Wilms' tumor 1 inhibits aromatase P450 expression in human cells and is downregulated in endometriosis vs. endometrium-derived stromal cells. American Society for Reproductive Medicine, 58th Annual Meeting, Seattle, WA, 2002 (Oral presentation). 102. Gurates B, S Sebastian, M Tamura, S Yang, J Zhou, Z Fang, S Amin, A Amsterdam, and Bulun SE: WT1 and DAX-1 regulate SF-1-mediated human P450arom gene expression in gonadal cells. The Endocrine Society, 84th Annual Meeting, San Francisco, CA. 2002. (Poster presentation). 103. Sebastian S, K Takayama, M Shozu and Bulun SE: Cloning and Functional Characterization of a Novel Promoter (I.7) of the Human CYP19 (AromataseP450) Gene that is Overexpressed in Breast Cancer and Regulated by GATA-2. The American Association of Cancer Research 92nd Annual Meeting, 2002 (Poster presentation). 104. Gurates B, S Sebastian, S Yang, M Tamura, Z Fang, S Amin and Bulun SE: A Novel response element in the human aromatase P450 promoter II confers regulation by transcription factors SF-1 and DAX-1 in Endometriosis and Ovary. The Society for Gynecologic Investigation, 49th Annual Meeting, Los Angeles, 2002 (Oral presentation). 105. Tamura M, S Sebastian, S Yang, B Gurates, and Bulun SE: Interleukin- duced cyclooxygenase-2 and prostaglandin E2 synthesis in primary human endometrial stromal cells is regulated by increased mRNA stability mediated by protein kinase A, nuclear factor- The Society for Gynecologic Investigation, 49th Annual Meeting, Los Angeles, 2002 (Poster presentation). 106. Yang SJ, ZJ Fang, B Gurates, S Amin, and Bulun SE: Regulation of human 17 hydroxysteroid dehydrogenase type 2 gene expression in human endometrial epithelial cells by the transcription factor Sp1. The Society for Gynecologic Investigation , 49th Annual Meeting, Los Angeles, 2002 (Oral presentation). 107. Tamura M, S Yang, B Gurates, Z Fang, S Sebastian and Bulun SE: Induction of cyclooxygenase-2 and prostaglandin E2 biosynthesis by epithelial cell derived factors is mediated mainly by p42/p44 mitogenactivated protein (MAP) kinase in stromal cells in endometrium. American Society for Reproductive Medicine, 57th Annual Meeting, Orlando, FL, 2001 (Oral presentation).

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108. Gurates B, S Yang, Z Fang, M Tamura, S Sebastian and Bulun SE: Transcriptional regulation of the CYP1A1 gene by dioxin in eutopic endometrial and endometriotic stromal cells. American Society for Reproductive Medicine, 57th Annual Meeting, Orlando, FL, 2001 (Oral presentation). 109. Fang Z, S Yang, M Tamura, B Gurates and Bulun SE: Treatment with the aromatase inhibitor letrozole significantly reduced the size of ectopic uterine implants. American Society for Reproductive Medicine, 57th Annual Meeting, Orlando, FL , 2001 (Oral presentation). 110. Yang S, Z Fang, B Gurates, and Bulun SE: Differential binding of C/EBP isoforms to aromatase promoter II in eutopic endometrial and endometriotic stromal cells. American Society for Reproductive Medicine, 57th Annual Meeting, Orlando, FL, 2001 (Oral presentation). 111. Sebastian S and Bulun SE: Physical mapping based on human genome project data reveals a highly complex genomic organization of the CYP19 (aromatase P450) gene. The Endocrine Society, 83rd Annual Meeting, Denver, CO, 2001 (Poster presentation). 112. Sebastian S, M Shozu, W Hsu, J Sarkey, R Schultz, K Neely and Bulun SE: Estrogen excess caused by gain of function mutations of the CYP19 (Aromatase)gene involving the chromosome 15Q21.2-Q21.3 region. The Endocrine Society, 83rd Annual Meeting, Denver, CO, 2001 (Oral presentation). 113. Tamura M, S Yang, Z Fang, S Sebastian and Bulun SE: Epithelial cell derived factors regulate the expression of Cyclooxygenase-1 and 2 in stromal cells in endometrium: a paracrine mechanism for prostaglandin formation. The Society for Gynecologic Investigation, 48th Annual Meeting, Toronto, Canada, 2001 (Oral presentation). 114. Gurates B, S Yang, J Zhou, Z Fang, S Sebastian, and Bulun SE: Regulation of CYP1A1 gene and enzyme activity of its product by dioxin in endometrial cells. The Society for Gynecologic Investigation, 48th Annual Meeting, Toronto, Canada, 2001 (Oral presentation). 115. Yang, SJ, ZJ Fang, B Gurates, J Miller, and Bulun SE: Stromal Cell Progesterone Receptors Mediate Stimulation of Epithelial 17β-HSD Type 2 Expression in Endometrium: Evidence for a Stromal Cell Defect Responsible for 17β- HSD Type 2 Deficiency in Endometriosis. The Society for Gynecologic Investigation, 48th Annual Meeting, Toronto, Canada. 2001 (Poster Presentation). 116. Fang, ZJ, SJ Yang, B Gurates, and Bulun SE: Use of transgenic knockout mice to understand the roles of estrogen and progesterone in the growth of ectopic uterine tissue as a model for endometriosis. American Society for Reproductive Medicine, 56th Annual Meeting, San Diego, CA,2000 (Oral Presentation). 117. Zhou, J and Bulun SE: C/EBPβ, C/EBPα and PPARγ stimulate aromatase P450 promoter II activity in human and murine adipose fibroblasts: part of an epithelial-stromal interaction in breast cancer. US Army Breast Cancer Research Program (Era of Hope), Atlanta, GA. 2000 (Poster). 118. Zhou, J and Bulun SE: TNFα and IL-11 Secreted by Malignant Breast Epithelial Cells Inhibit Adipocyte Differentiation by Selectively Inhibiting C/EBPα and PPARγ. US Army Breast Cancer Research Program (Era of Hope), Atlanta, GA. 2000 (Poster). 119. Bulun SE, K Zeitoun, L Noble, K Takayama, and G Attia: Aromatase: A Key Molecule in Pathophysiology of Endometriosis and A Therapeutic Target. The Endocrine Society, 81st Annual Meeting, San Diego, CA. 1999 (Invited Speaker). 120. Bulun SE, CS Mao, JA Brasel, and EK Neely: Treatment of gynecomastia and hypogonadism in disorders of excessive estrogen formation using an aromatase inhibitor. The Endocrine Society, 81st Annual Meeting, San Diego, CA. 1999 (Oral presentation). 121. Zeitoun K, G Attia, D Michael, H Murakami, BR Carr, and Bulun SE: A novel inhibitory region (-517/-694 bp) in aromatase P450 confers tissue-specific inhibition of aromatase expression in eutopic endometrium. The Society for Gynecologic Investigation, 46th Annual Meeting, Atlanta, GA, 1999 (Oral presentation) (President’s Presenter Award). 122. Attia G, K Zeitoun, BR Carr, and Bulun SE: Differential expression of progesterone receptor isoforms in eutopic endometrium and endometriosis. The Society for Gynecologic Investigation, 46th Annual Meeting, Atlanta, GA, 1999 (Oral presentation). 123. Zeitoun K, K Takayama, MD Michael, M Putman, A Johns, H Sasano, BR Carr and Bulun SE: Aromatase expression in endometriosis and its inhibition in endometrium are regulated by competitive action of two transcription factors: steroidogenic factor-1 (SF1) and chicken ovalbumin upstream promoter-transcription factor (COUP-TF). The American Society for Reproductive Medicine, 54th Annual Meeting, San Francisco, CA, 1998 (1998 ASRM-SRE Prize Paper Award). 124. Zeitoun K, A Johns, M Putman, AS Andersson, BR Carr and Bulun SE: Defective inactivation of estradiol in

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endometriosis in relation to deficient 17-HSD type 2 expression. IV World Congress on Endometriosis, Quebec City, Canada, 1998 (Oral presentation). 125. Meng L, K Zeitoun, K Takayama, H Sasano and Bulun SE: Breast cancer cells inhibit adipocyte differentiation: mechanism of desmoplastic reaction. The Endocrine Society, 80th Annual Meeting, New Orleans, LA, 1998 (Poster presentation). 126. Shozu M, K Takayama and Bulun SE: Mutation in 5-flanking region of CYP19 gene causes excessive peripheral aromatase expression in boy with gynecomastia. The Endocrine Society, 80th Annual Meeting, New Orleans, LA, 1998 (Oral presentation). 127. Zeitoun K, M Ebaugh, BR Carr and Bulun SE: 17-HSD type 3 expression in a persistent ovarian tumor giving rise to recurrent gestational virilization. The Endocrine Society, 80th Annual Meeting, New Orleans, LA, 1998 (Oral presentation). 128. Zeitoun K, N Moghrabi, IM Rosenthal, F Straus, H Sasano, K Takayama, S Andersson and Bulun SE: Aberrant expression of 17-HSD type 3 in adrenal mass associated with isosexual precocity in a boy. The Endocrine Society, 80th Annual Meeting, New Orleans, LA, 1998 (Oral presentation). 129. Zeitoun K, K Takayama, RT Gunby, BR Carr and Bulun SE: Treatment of severe endometriosis with an aromatase inhibitor: a novel indication and its molecular basis. The Society for Gynecologic Investigation, 45th Annual Meeting, Atlanta, GA 1998 (Poster presentation). 130. Agarwal VR, S Sasano, K Takayama, IM Rosenthal, R Walton, ER Simpson and Bulun SE: Excessive levels of aromatase P450 and its transcripts in breast adipose tissue of a girl with pubertal macromastia. The Endocrine Society, 79th Annual Meeting, Minneapolis, MN, 1997 (Poster presentation). 131. Shozu M, Bulun SE, Y Zhao and ER Simpson: Expression of a novel exon I of the aromatase gene: exon I.6. The Endocrine Society, 79th Annual Meeting, Minneapolis, MN, 1997 (Poster presentation). 132. Zeitoun KM, K Takayama, N Moghrabi, M Putman, BR Carr and Bulun SE: Conversion of estrone to estradiol is increased in endometriosis compared with the endometrium. The Society for Gynecologic Investigation, 44th Annual Meeting, San Diego, CA 1997 (Poster presentation). 133. Noble LS, K Takayama, JM Putman, DA Johns, BR Carr and Bulun SE: Molecular basis for prostaglandin E2 induction of local estrogen biosynthesis in endometriosis. The American Society for Reproductive Medicine, 52nd Annual Meeting, Boston, MA, 1996 (Plenary lecture, 1996 ASRM-SRE Prize Paper Award). 134. Noble LS, ER Simpson, JM Putman, A Johns and Bulun SE: Aromatase P450 expression in endometriotic implants and endometriosis-derived stromal cells in culture. 10th International Congress of Endocrinology, San Francisco, CA, 1996 (Poster presentation). 135. Agarwal VR, Bulun SE and ER Simpson: Alternatively spliced transcripts of the aromatase cytochrome P450 (CYP19) gene in adipose tissue of breast cancer patients. 10th International Congress of Endocrinology, San Francisco, CA, 1996 (Poster presentation). 136. Noble LS, ER Simpson, VR Agarwal, A Johns and Bulun SE: Regulation of aromatase expression in cultured stromal cells derived from endometriosis. The Society for Gynecologic Investigation, 43rd Annual Meeting, Philadelphia, PA, 1996 (Oral presentation). 137. Agarwal VR, ER Simpson and Bulun SE: Use of alternative promoters of the aromatase P450 gene in human breast carcinogenesis. Cold Spring Harbor Meetings, Cancer Cells: Mechanism of Eukaryotic Transcription, New York, 1995 (Poster presentation). 138. Bulun SE, J Rink, G Sharda, S Sharma and ER Simpson: Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast. The Endocrine Society, 77th Annual Meeting, Washington, DC, 1995 (Poster presentation). 139. Zhao Y, JE Nichols, Bulun SE and ER Simpson: Aromatase gene expression in human adipose stromal cells: a Jak/STAT signalling pathway is involved in regulation by cytokines. The Endocrine Society, 77th Annual Meeting, Washington, DC, 1995 (Oral presentation). 140. Crichton MB, Y Zhao, JE Nichols, Bulun SE and ER Simpson: Breast cancer cell lines and tumors express cytokines which are stimulatory of aromatase expression in adipose tissue. The Endocrine Society, 77th Annual Meeting, Washington, DC, 1995 (Poster presentation). 141. Bulun SE, JJ Van Wyk, G Jones and ER Simpson: Molecular basis for gynecomastia associated with aromatase expression in hepatocellular carcinoma. The Endocrine Society, 77th Annual Meeting, Washington, DC, 1995 (Oral presentation). 142. Noble LS, ER Simpson, A Johns and Bulun SE: Detection of aromatase P450 transcripts in endometriosis. The Society for Gynecologic Investigation, 42nd Annual Meeting, Chicago, IL, 1995 (SGI President’s Poster Award).

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143. Nichols JE, Bulun SE and ER Simpson: Aromatase activity in adipose stromal cells in culture is markedly stimulated by interleukin-11. The Society for Gynecologic Investigation, 42nd Annual Meeting, Chicago, IL, 1995 (Poster presentation). 144. Bulun SE, Y Ito, M Bryant and ER Simpson: Molecular basis for increased extraglandular aromatization of plasma nd C19 steroids resulting in prepubertal gynecomastia. The Society for Gynecologic Investigation, 42 Annual Meeting, Chicago, IL, 1995 (Oral presentation). 145. Nichols JE, Bulun SE and ER Simpson: Aromatase activity of adipose stromal cells in culture is markedly stimulated by conditioned media from MCF-7 and T-47D breast cancer cell lines. The Endocrine Society, 76th Annual Meeting, Anaheim, CA, 1994 (Oral presentation). 146. Bulun SE, K Economos and ER Simpson: CYP19 (aromatase cytochrome P450) gene expression in human malignant endometrial tumors. The Endocrine Society, 76th Annual Meeting, Anaheim, CA, 1994 (Poster presentation). 147. Bulun SE, CH Albini, AM Brodie, MH McGillivray, W Yu and ER Simpson: Quantification of aromatase cytochrome P450 transcripts in a testicular tumor and breast tissue samples from a prepubertal boy with gynecomastia and Peutz-Jeghers syndrome using competitive RT-PCR technology. The Endocrine Society, 76th Annual Meeting, Anaheim, CA, 1994 (Poster presentation). 148. Bulun SE, M Crichton and ER Simpson: Aromatase cytochrome P450 expression in adipose stromal cells is regulated by medroxyprogesterone acetate and RU486. The Society for Gynecologic Investigation, 41st Annual Meeting, Chicago, IL, 1994 (Oral presentation). 149. Bulun SE and ER Simpson: Regulation of aromatase cytochrome P450 gene expression is directed by the same promoter in fetal and adult ovaries as in estrogen-producing ovarian sex cord tumors. The American Fertility Society, Montreal, Canada, 1993 (Oral presentation). 150. Bulun SE and ER Simpson: Levels of aromatase cytochrome P450 transcripts in adipose tissue of women at various body sites increase with advancing age. The Endocrine Society, 75th Annual Meeting, Las Vegas, NV, 1993 (Poster presentation). 151. Bulun SE, ER Simpson and RA Word: Quantification of aromatase cytochrome P450 transcripts in uterine leiomyomas and proximal myometrial tissues by competitive polymerase chain reaction technology. The Society for Gynecologic Investigation, 40th Annual Meeting, Toronto, Canada, 1993 (Oral presentation). 152. Bulun SE, TM Price and ER Simpson: Quantification of breast adipose tissue aromatase cytochrome P450 mRNA by a specific competitive polymerase chain reaction in patients with breast cancer. The American Fertility Society, New Orleans, LA, 1992 (Plenary lecture, 1992 AFS-SRE Prize Paper Award). 153. Bulun SE, TM Price, J Aitken and ER Simpson: Distribution of aromatase cytochrome P450 transcripts in adipose tissue from human breast quadrants correlates with site of tumor. 9th International Congress of Endocrinology, Nice, France, 1992 (Poster presentation). 154. Bulun SE, MW Kilgore, WP Zeller and IR Rosenthal: Alternative splicing of aromatase P450 transcripts in feminizing tumor of Peutz-Jeghers syndrome. The Endocrine Society, 74th Annual Meeting, San Antonio, TX, 1992 (Oral presentation). 155. Bulun SE, ER Simpson and MS Mahendroo: Local estrogen biosynthesis in adipose tissue from human breast quadrants correlates with the site of malignancy independent of various prognostic factors. Basic and Clinical Aspects of Aromatase: The Third International Conference on Aromatase, Bologna, Italy, 1992 (Poster presentation). 156. Bulun SE, O Dogan and K Crickard: Ag staining of nucleolar organizer regions assists to differentiate between benign, borderline, and malignant epithelial ovarian tumors. The Society for Gynecologic Investigation, 39th Annual Meeting, San Antonio, TX, 1992 (Poster presentation). 157. Bulun SE, TM Price, MS Mahendroo and ER Simpson: Failure to detect aromatase cytochrome P450 mRNA in human endometrium by means of polymerase chain reaction technology. The Society for Gynecologic Investigation, 39th Annual Meeting, San Antonio, TX, 1992 (Oral presentation).

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