ORIGINAL RESEARCH

Prenatal Dexamethasone for CongenitalAdrenal Hyperplasia

An Ethics Canary in the Modern Medical Mine

Alice Dreger & Ellen K. Feder & Anne Tamar-Mattis

Received: 11 April 2012 /Accepted: 14 May 2012# The Author(s) 2012. This article is published with open access at Springerlink.com

Abstract Following extensive examination of pub-lished and unpublished materials, we provide a historyof the use of dexamethasone in pregnant women at riskof carrying a female fetus affected by congenital adrenalhyperplasia (CAH). This intervention has been aimed atpreventing development of ambiguous genitalia, theurogenital sinus, tomboyism, and lesbianism. We mapout ethical problems in this history, including: mislead-ing promotion to physicians and CAH-affected families;de facto experimentation without the necessary protec-tions of approved research; troubling parallels to thehistory of prenatal use of diethylstilbestrol (DES); andthe use of medicine and public monies to attempt

prevention of benign behavioral sex variations. Criticalattention is directed at recent investigations by the U.S.Food and Drug Administration (FDA) and Office ofHuman Research Protections (OHRP); we argue thatthe weak and unsupported conclusions of these inves-tigations indicate major gaps in the systems meant toprotect subjects of high-risk medical research.

Keywords Congenital adrenal hyperplasia .

Dexamethasone .Medical ethics . Gender identity .

Sexual orientation . Human subjects research

Introduction/Our Backgrounds

In this article, we provide a condensed history of the useof prenatal dexamethasone for congenital adrenal hyper-plasia, with an eye toward the ethically problematicaspects of this history. Congenital adrenal hyperplasia(CAH) is a disease of the endocrine system that cancause virilization (i.e., development of masculine traits)in female fetuses. In an attempt to prevent CAH-affectedfemale fetuses from developing in a sexually atypicalfashion, some physicians treat pregnant women “at risk”for having an affected daughter with the steroid dexa-methasone. This intervention starts as soon as pregnan-cy is confirmed and continues throughout the pregnancyif the fetus is ultimately diagnosed as a CAH-affectedfemale. If—several weeks into the dosing—the fetus isdetermined to be male or not CAH-affected, the inter-vention is immediately stopped, because the intention is

Bioethical InquiryDOI 10.1007/s11673-012-9384-9

A. Dreger (*)Clinical Medical Humanities and Bioethics,Program in Medical Humanities and Bioethics,Feinberg School of Medicine, Northwestern University,750 N Lake Shore Dr., Suite 625,Chicago, IL 60611, USAe-mail: a-dreger@northwestern.edu

E. K. FederDepartment of Philosophy and Religion,American University,Washington, DC, USAe-mail: efeder@american.edu

A. Tamar-MattisAdvocates for Informed Choice,Cotati, CA, USAe-mail: director@aiclegal.org

only to alter the course of development in CAH-affectedfemales.

Thisuseof dexamethasonewas first described in1984inTheJournalofPediatricsbyMichelDavidandMague-loneForest, French clinician-researchers.David andFor-est reported apparent effectiveness of prenataldexamethasone in eliminating genital virilization in asingle girl affected by CAH (David and Forest 1984). Inthe nearly three decades since David and Forest’s paper,many specialists have come to believe that prenatal dexa-methasone for CAH constitutes the standard of care. A2000–2001 survey of members of the European Societyfor Paediatric Endocrinology, representing 125 institu-tions, found that, “[i]n 57 % of the centres prenatal diag-nosis and treatment [of CAH with dexamethasone] areroutine” (Riepe et al. 2002, 199). A 2010 ContinuingMedical Education review article in the Obstetrical andGynecological Survey concluded: “Given the data avail-able at this moment, antenatal treatment with corticoste-roids is recommended” (Vos and Bruinse 2010, 203).

But what data are “available at this moment” suchthat prenatal dexamethasone for CAH can be recom-mended to obstetricians, and recommended by them toprospective patients?

A systematic review and meta-analysis of this inter-vention, published in 2010 in Clinical Endocrinology,indicated that a search of the literature “identified 1083candidate studies for review; of which, only four studieswere confirmed eligible” for serious scientific consider-ation (Fernández-Balsells et al. 2010, 438). That is to say,as late as 2010, less than one half of one percent ofpublished “studies” of this intervention were regardedas being of high enough quality to provide meaningfuldata for a meta-analysis. Even these four studies were oflow quality:

All the eligible studies were observational andwere conducted by two groups of investigators(one from the US and one from Europe).… Stud-ies lacked details regarding the use of methodo-logical features that protect against bias. None ofthe studies reported blinding of the outcome asses-sors to the exposure (i.e., the researchers estimat-ing each patient’s degree of virilization). Loss tofollow-up was, in most cases, substantial(Fernández-Balsells et al. 2010, 438).

In spite of at least a thousand pregnant womenlikely having been exposed by the time of the review,the four studies judged worthy of inclusion in the

meta-analysis covered only 325 pregnancies. Evenmore stunning, the meta-analysis revealed, “therewere no data on long-term follow-up of physical andmetabolic outcomes in children exposed to dexameth-asone” prenatally for CAH (Fernández-Balsells et al.2010, 436, emphasis added). It was not that the dataabout long-term physical and metabolic outcomeswere unclear; there simply were none available.

Today, some clinicians promote prenatal dexametha-sone for CAH as “an excellent example of pharmaco-logical therapy during pregnancy” (Rosner et al. 2006,803) and even as “a paradigm of prenatal diagnosis andtreatment” (Nimkarn and New 2010a, 5). Yet the Endo-crine Society Task Force that had commissioned the2010meta-analysis concluded: “The evidence regardingfetal and maternal sequelae … is of low or very lowquality due to methodological limitations and samplesizes” (Speiser et al. 2010a, 4137). This would hardlyseem to qualify prenatal dexamethasone for CAH as “anexcellent example” or a “paradigm” of a prenatal phar-macological intervention. Indeed, for lack of qualityclinical studies, the 2010 Task Force could not evensay with any confidence whether prenatal dexametha-sone works to reduce genital virilization. Notice thespecific qualifications included in the Task Force’s state-ment on efficacy: “[T]he groups advocating andperforming prenatal treatment appear to agree that itis effective in reducing and often eliminating virilizationof female fetal genitalia and that the success rate is about80–85%” (Speiser et al. 2010a, 4138, emphasis added).

Regardless of some people’s enthusiastic endorse-ments of the intervention, we show below that ethicaldebates within medicine about prenatal dexametha-sone for CAH are actually not new. Those internaldebates, however, have focused on potential risksand benefits to mothers and children exposed. Thereare a number of other ethical problems in the history ofthis intervention also deserving of attention, including:de facto experimentation on fetuses and pregnantwomen, largely outside of prospective long-term trialsand without adequate informed consent; failure toappropriately collect and publish evidence when pro-moting and providing a high-risk intervention; use ofmedicine and public monies for research to preventbenign behavioral sex variations, including tomboy-ism and lesbianism (cf. Murphy 1997); and inadequa-cy in the United States of systems designed to protectsubjects of medical experimentation, including espe-cially pregnant women and their offspring.

Bioethical Inquiry

In the United States, the use of prenatal dexametha-sone remains “off-label.” This means that the indicationhas never received approval by the Food and DrugAdministration (FDA).1 Nonetheless, we want to beclear: The problem we see with the use of prenataldexamethasone for CAH is not per se that it is an off-label use; it is rather that—as this paper documents—prenatal dexamethasone for CAH has sometimes beenpromoted to prospective patients and clinicians in mis-leading ways, and sometimes promoted for uses that arenot legitimately medical (e.g., for the prevention oftomboyism and lesbianism). Furthermore, this interven-tion—intended to alter the course of fetal development—has been “studied” in ways so slipshod as to breachprofessional standards of medical ethics.

We come to this work as history, philosophy, andlegal scholars interested in the medical treatment ofchildren with atypical sex, but also as women who havelong advocated clinical reform in this general area. Latein 2009, clinicians working in the pediatric care ofchildren born with sex anomalies made one of us(Dreger) aware of their growing alarm about prenataldexamethasone for CAH. These clinicians wereconcerned that pregnant women at risk for havingdaughters with CAH were being given prenatal dexa-methasone without being informed that (a) this use hasconsistently been labeled experimental by expert panels;(b) benefits and risks have not been established, due toinadequate scientific study; and (c) some children whohad been exposed in utero were being studied retrospec-tively, in many cases years later, by the very clinicianswho had been (andwere still) actively promoting the useto pregnant women as “safe for mother and child,” tofind out what the risks might really be.

Dreger (a historian) then reviewed the medical lit-erature as well as Internet-based advertisements direct-ed at affected families and became quite concerned. InDecember 2009 and January 2010, respectively,Dreger and UCLA pediatric geneticist Eric Vilainseparately asked Mount Sinai School of Medicinepediatric endocrinologist Maria New, the most prom-inent promoter of this intervention, about the informedconsent process she used. New is a highly distin-guished pediatric endocrinologist and member of theNational Academy of Sciences. By 2003, she hadalready publicly taken credit for having “treated”more

than 600 pregnant women with dexamethasone in anattempt to prevent virilization in CAH-affected femalefetuses (Kitzinger 2003), putting her efforts in this areawell beyond any other clinical researcher’s (see alsoNew et al. 2001). Dreger’s preliminary research indi-cated that, even while obtaining a federal grant prom-ising to determine the actual safety and efficacy ofprenatal dexamethasone for CAH through retrospec-tive follow-up studies, New was functioning as auniquely aggressive promoter of the interventionamong parents and clinicians, repeatedly describingthis intervention as “safe for mother and child” (New2010a, ¶4). But when Dreger and Vilain attempted toask New about informed consent, both were rebuffedby New. Indeed, at the Miami medical conferencesession where Vilain pressed the issue (at New2010b), New publicly admonished Vilain that hisquestion to her was inappropriate.

Dreger then asked colleagues in bioethics and alliedfields to join with her in raising concerns to the U.S.government regarding the potential failure to protect therights of these women and their offspring. The secondauthor of this paper (Feder) became the correspondingauthor on the resulting (February 2010) letters of con-cern from a total of 32 academicians to the Office ofHuman Research Protections (OHRP) and the FDA.The third author (Tamar-Mattis) handled most of oursubsequent communications with federal agencies andconducted additional legal research.

In September 2010, the OHRP and FDA informedus they could find nothing worth pursuing further. TheOHRP decided that abuse had not occurred because:(a) at least some of the pregnant women had beenenrolled in IRB-approved studies when given the drugat Weill Cornell Medical College, where most of theinterventions appear to have occurred while Newworked there; (b) follow-up studies conducted atMount Sinai School of Medicine under New had beenIRB-approved; and (c) the fetal intervention itself doesnot require IRB oversight. The FDA explained that (toour surprise) regulations allow a clinician to promotean off-label use—even an experimental use intendedto alter fetal development—as “safe and effective” solong as the clinician does not simultaneously work forthe drug maker or count as an FDA-approved investi-gator of the drug (Borror 2010). (Dreger has made theagencies’ full responses available at fetaldex.org.)Nevertheless, we show here that the material generat-ed by the government’s own investigations—along

1 For an analysis of the problems with off-label usages, seeDresser and Frader (2009).

Bioethical Inquiry

with further scholarly inquiry on our part—appearactually to confirm the concerns we expressed at theoutset, suggesting a major failure of the layered sys-tems designed to protect subjects of research, especial-ly pregnant women and their fetuses.

Because the following history necessarily focusesattention on the actions of Maria New, we want to besure that our readers appreciate that New’s career hasincluded critically important research and clinical carethat has improved the lives, health, and fertility of a verylarge population. Her promotion of prenatal dexameth-asone for CAH was no doubt motivated by a desire toimprove the lives of her patients. The same beneficentattitude was likely present in all or most of the clinicianswho used prenatal dexamethasone for CAH. But it isworth remembering that many cases in the history ofmedicine now rightly understood as ethically problem-atic were carried out by clinical researchers with goodintentions (Eder 2011; Reverby 2009; Skloot 2010).

It has been impossible for us not to be aware that, aswe have researched this fetal intervention, the medicalworld has beenmarking the 40th anniversary of the 1971publication of a study reporting a relatively high numberof occurrences of a rare vaginal cancer in girls andyoung women who had been exposed in utero to dieth-ylstilbestrol (DES). It was this small 1971 study—eightsubjects with adenocarcinoma of the vagina matched to32 untreated controls—that marked the beginning of theend of DES administration to pregnant women (Herbst,Ulfelder, and Poskanzer 1971). DES treatment duringpregnancy had had admirable intentions, including pri-marily the prevention of miscarriage. Already by 1953,DES had actually been found ineffective for miscarriageprevention, but doctors continued to prescribe it to preg-nant women anyway. Over the years, millions of fetuseswere exposed, putting females and males at increasedrisk for rare cancers, genital anomalies, reproductiveproblems, etc. (Goodman, Schorge, and Greene 2011).

As we have spoken with others about how the use ofprenatal dexamethasone for CAH has played out, it hasbeen our experience that many have been skeptical that aDES-like scenario could occur with prenatal dexametha-sone for CAH after what physicians learned from DES.Wefindourselveswonderingwhether it is theassumptionthat “we’ll never do that again” that paradoxically hasblinded many clinicians to the striking parallels betweenDES and prenatal dexamethasone for CAH: Both DESand dexamethasone are powerful synthetic hormones; inboth cases the practice involved administration of the

intervention starting early in pregnancy; both were intro-duced into medical practice without much study as toefficacy and safety (Dreger et al. forthcoming).

Three strikingdifferencesbetween these interventionsare that: (1) this poorly studied yet widespread use ofprenatal dexamethasone is happening after the lessonssupposedly learned fromDES; (2) while DES was neverintended to alter fetal development, prenatal dexametha-sone forCAHhas explicitly aimed to do so; and (3)whileDESwas aimedatpreventing fetal death,dexamethasoneis directed at preventing something we would hopemostpeople would understand to be substantially less dire,namely the development of atypical sex.

Yet rather than suggesting that the case of prenataldexamethasone for CAH should be understood as oneof the “big” stories of the history of medicine (likeDES), we are suggesting something more disturbing:that this case appears to be representative of problemsendemic in modern medicine, problems that threatenthe health, lives, and rights of patients who continue tobecome unwitting subjects of (problematic) medicalexperimentation. Because so many systems of protec-tion appear to have failed these women and children,we fear that prenatal dexamethasone for CAH is acanary in the modern medical mine.

CAH’s Effects and the Goals of Using PrenatalDexamethasone

Congenital adrenal hyperplasia (CAH) is a geneticdisease involving malfunction of the adrenal glands,endocrine organs that contribute to the production ofsex steroids. CAH can occur in both males andfemales and can cause a number of metabolic prob-lems, some of which may lead to postnatal adrenalcrisis and death if left untreated. Because some formsof CAH are very dangerous, all U.S. states requirenewborn screening for CAH.

The prenatal administration of dexamethasone, a po-tent synthetic steroid of the glucocorticoid class, cannotprevent an affected child from being born with CAH.The intervention is aimed instead at causing CAH-affected female fetuses to develop in a more female-typical fashion than they otherwise might. Androgenscontribute to sex differentiation, including in the brainand genitals; relatively low prenatal levels ordinarilyresult in a more female-typical development; relativelyhigh levels usually result in male-typical development.

Bioethical Inquiry

In certain forms of CAH—including 21-hydroxylasedeficiency (21-OHD CAH), i.e., the type of CAH mostat issue here—the prenatal production of high levels ofandrogens may result in a genetic female (46,XX) fetusdeveloping along a more masculine pathway neurolog-ically and genitally. Prenatal dexamethasone is meant toengineer the CAH-affected female fetus’s hormonalsystem to be typically female.

The intensity of CAH’s effects on developing femalesvaries. An affected genetic-female child might be bornfairly female-typical, or she may be born with a largeclitoris, labia that fuse and appear to form a scrotum,and an occluded or even absent lower vagina. Someaffected genetic females have developed suchmasculinegenitalia that theyhavebeenassumedatbirth tobe typicalmales and have been raised as boys (Eder 2011; Lee andHouk2010).Newbornscreening forCAH,aimedprimar-ily at saving lives, has greatly reduced the likelihood ofsuch children’s conditions going undetected.

Atypical clitorises and labia generally require nomed-ical intervention for health.Despite evidence that electivegenitoplasty may harm a girl (Crouch et al. 2004), pedi-atric urologists often perform surgery to “feminize” atyp-ical clitorisesand labia forwhat theycall“social reasons,”includingpromotionofparent–childbonding.Theydosoevenwhile admittingwe lack evidence that this approachis necessary or effective (Lee et al. 2006).

Some CAH-affected girls are also born with a uro-genital sinus, a condition in which the urethra andvagina are joined together. This creates potential forrepetitive infections and also presents problems for sex-ual intercourse. Thus the urogenital sinus has tradition-ally been treated with pediatric surgery. It represents partof what prenatal dexamethasone is meant to prevent.

Women “at risk” of giving birth to a CAH-affecteddaughter are most often identified because they havealready given birth to a CAH-affected child. Others areidentified through genetic screening. Because “the peri-od during which the genitalia of a female fetus maybecome virilized begins only 6 [weeks] after concep-tion, treatment must be instituted as soon as the womanknows she is pregnant” (Speiser et al. 2010a, 4137; cf.Nimkarn and New 2007). Although this intervention issometimes termed “low-dose therapy” (New 2010c),researchers estimate that “the effective glucocorticoiddoses reaching the fetus are 60–100 times physiologic”(Miller 2008, 17), meaning this intervention exposes thedeveloping fetus to 60 to 100 times the normal level ofglucocorticoids. The potential harms of prenatal

dexamethasone represent a growing source of concernfor clinical researchers because emerging research indi-cates glucocorticoids may alter “fetal programming,”potentially resulting in serious metabolic problems thatwill not become apparent until adulthood (Hirvikoski etal. 2007; Marciniak et al. 2011). Some animal studies,for example, suggest long-term risk to the cardiovascu-lar system (Lajic, Nordenström, and Hirvikoski 2011).

CAH is an autosomal recessive disorder, so offspringof carrier parents have a 1 in 4 chance of having CAHand thus only a chance of 1 in 8 of being a CAH-affectedfemale (since only half of the 1 in 4 will be females).While recent advances now may enable determinationof fetal sex by the seventh week (Devaney et al. 2011),before 2011 the sex status of fetuses could not be deter-mined reliably before 10 to 12 weeks. As a conse-quence, about 7 out of 8 (87.5 percent) of theindividuals who have been exposed to many weeks ofprenatal dexamethasone—at 60 to 100 times normallevels—never even had the condition that was beingtargeted with the prenatal intervention. These individu-als have been “necessarily” exposed to risk in order totry to engineer the development of the 1 in 8 who wouldbe CAH-affected females. Many of the clinicians whohave raised ethical concerns about prenatal dexametha-sone for CAH have specifically been concerned aboutthe 87.5 percent (those 7 out of 8) exposed to the risk offirst-trimester glucocorticoid “therapy” who stood nochance to benefit (e.g., Frias et al. 2001; Hirvikoski etal. 2007; Miller 2008; Speiser et al. 2010a).

Most clinicians who have written about prenataldexamethasone have spoken of its purpose as theprevention of ambiguous genitalia and the urogenitalsinus. (Sometimes they speak of the urogenital sinusas part of “ambiguous genitalia,” and sometimes theyspeak of these as two sets of concerns.) But interest-ingly, some clinicians also speak of prenatal dexame-thasone’s purpose as the prevention of feminizinggenital surgeries. So one elective risky intervention(prenatal dexamethasone) has been represented as nec-essary to prevent another (feminizing genital surger-ies) (Nimkarn and New 2010a). Notably, in 2006, amajor consensus of the American and European pedi-atric endocrine groups, known as “the Chicago con-sensus,” urged a more conservative approach tosurgeries for genital anomalies, stating that, for girls,“surgery should only be considered in cases of severevirilization” (Lee et al. 2006, e491). But this recom-mendation does not appear to have had much (if any)

Bioethical Inquiry

effect on the promotion of prenatal dexamethasone asa preventive to “feminizing” surgery.

Studieshaveshownthatgirlswith21-OHDCAHexhibitincreased ratesofwhat clinicians call“behavioralmasculin-ization,” i.e., behaviors that are more male-typical. Thesegirls are, on average, more interested in boy-typical play,hobbies, and subjects than non-affected females, less inter-ested in becomingmothers, andmore likely to grow up tobe lesbian or bisexual (Meyer-Bahlburg 1999; Meyer-Bahlburg et al. 2006). The rate of adult identification asmale is significantly higher in this group than in thegeneral population of people with an XX karyotype;clinician-researchers report that about 5 percent ofCAH-affected genetic-females may ultimately self-identify as male (Dessens, Slijper, and Drop 2005).For this reason, some clinicians have considered recom-mending raising highly virilized 46,XX CAH-affectedbabies as boys (Lee and Houk 2010; cf. Eder 2011).

Although many researchers have hinted that prenataldexamethasonemight be good for preventing the “behav-ioralmasculinization” associatedwithCAH (e.g., Lajic etal.1998), thispotential“benefit”hasbeenspelledoutmostexplicitly in the work of Maria New (Dreger, Feder, andTamar-Mattis 2010).Writingwith another pediatric endo-crinologist in the2010Annalsof theNewYorkAcademyofSciences in an article that disregarded the 2006 Chicagoconsensus, New summed up the situation thus:

Without prenatal therapy, masculinization of ex-ternal genitalia in females is potentially devastat-ing. It carries the risk of wrong sex assignment atbirth, difficult reconstructive surgery, and subse-quent long-term effects on quality of life. Gender-related behaviors, namely childhood play, peerassociation, career and leisure time preferencesin adolescence and adulthood, maternalism [inter-est in being a mother], aggression, and sexualorientation become masculinized in 46,XX girlsand women with 21HOD deficiency. … Genitalsensitivity impairment and difficulties in sexualfunction in women who underwent genitoplastyearly in life have likewise been reported. We an-ticipate that prenatal dexamethasone therapy willreduce the well-documented behavioral masculin-ization and difficulties related to reconstructivesurgeries (Nimkarn and New 2010a, 9).

Among those advocating prenatal dexametha-sone, New seems to have been particularlyconcerned that CAH-affected girls may fail to

grow up to be heterosexual wives and mothers.Speaking to a group of parents of children withCAH in 2001 at a meeting organized by theCARES Foundation, New showed a photo of agirl with ambiguous genitalia and said:

The challenge here is … to see what could bedone to restore this baby to the normal femaleappearance which would be compatible with herparents presenting her as a girl, with her eventu-ally becoming somebody’s wife, and having nor-mal sexual development, and becoming amother. And she has all the machinery for moth-erhood, and therefore nothing should stop that, ifwe can repair her surgically and help her psy-chologically to continue to grow and develop asa girl (New 2001a).

In a 1999 paper entitled “What Causes Low Ratesof Child-Bearing in Congenital Adrenal Hyperpla-sia?”, New’s chief collaborator in psychoneuroendo-crine studies of CAH, Heino Meyer-Bahlburg ofColumbia University, noted:

CAH women as a group have a lower interestthan controls in getting married and performingthe traditional child-care/housewife role. Aschildren, they show an unusually low interestin engaging in maternal play with baby dolls,and their interest in caring for infants, the fre-quency of daydreams or fantasies of pregnancyand motherhood, or the expressed wish of expe-riencing pregnancy and having children of theirown appear to be relatively low in all agegroups. (Meyer-Bahlburg 1999, 1845–1846).

Meyer-Bahlburg posited that “[l]ong term follow-up studies of the behavioral outcome will show wheth-er [prenatal] dexamethasone treatment also preventsthe effects of prenatal androgens on brain and behavior”(1999, 1846).

Surprisingly, results from our Freedom of Informa-tion Act (FOIA) requests—made as part of our attemptto understand this history—indicate that the U.S. Na-tional Institutes of Health (NIH) have fundedNew to seewhether prenatal dexamethasone “works” to make moreCAH-affected girls straight and interested in havingbabies. New’s 1996 grant application states that

genital abnormalities and often multiple correc-tive surgeries needed affect social interaction,self image, romantic and sexual life, and fertility.

Bioethical Inquiry

As a consequence, many of these patients, and themajority of women with the salt-losing variant [ofCAH], appear to remain childless and single. Pre-ventive prenatal dexamethasone exposure isexpectedto improve thissituation(New1996a,38).

New’s NIH grant application specifically promisedto try to determine “the success of DEX in suppressingbehavioral masculinization” (New 1996b, 17).

A Long History of Ineffective Calls for Ethical,Scientifically Rigorous Studies

The 2010 systematic review and meta-analysis of pre-natal dexamethasone for CAH (mentioned in our intro-duction) was commissioned by an Endocrine SocietyTask Force charged with developing new consensusguidelines for the treatment of CAH. That Task Forcewas in turn co-sponsored by the American Academy ofPediatrics, the Lawson Wilkins Pediatric Endocrine So-ciety, the European Society for Paediatric Endocrinolo-gy, the Society of Pediatric Urology, the EuropeanSociety of Endocrinology, the CARES Foundation,and the Androgen Excess and PCOS Society. Basedon the systematic review and meta-analysis, in its 2010practice guidelines the Task Force concluded

that prenatal therapy continue to be regarded asexperimental. … We suggest that prenatal thera-py be pursued through protocols approved byInstitutional Review Boards [i.e., ethics commit-tees] at centers capable of collecting outcomesdata on a sufficiently large number of patients sothat risks and benefits of this treatment can bedefined more precisely (Speiser et al. 2010a,4137, emphasis added).

The named authors of this 2010 consensus (includ-ing Meyer-Bahlburg) appeared to have recognized thattheir call for use only within scientifically-meaningfulclinical trials pre-approved by ethics committees wasnot novel. In fact, expert panels have consistentlyjudged prenatal dexamethasone for CAH to be riskyand experimental. In 2002, a joint statement from theLawson Wilkins Pediatric Endocrine Society and theEuropean Society for Paediatric Endocrinology hadalready said something similar—even stronger:

We believe that this specialized and demandingtherapy should be undertaken by designated

teams using nationally or multinationally ap-proved protocols, subject to institutional reviewboards [IRBs] or ethics committees in recog-nized centers. Written informed consent mustbe obtained. … Families and clinicians shouldbe obliged to undertake prospective follow-up ofprenatally treated children whether they haveCAH or not. The data should be entered into acentral database audited by an independent safetycommittee. (Joint LWPES/ESPE CAH WorkingGroup 2002, 4049, emphasis added).

And a year earlier, in a tense exchange of letterswith New in the journal Pediatrics, representatives ofthe Section on Endocrinology and Committee on Ge-netics of the American Academy of Pediatrics hadadmonished New that

it remains the physician’s ethical obligation toremain very cautious, even if using lower doses.The fact that only 1 in 8 treated pregnancies maybenefit from the therapy confounds this equationeven further. There is much information on theeffect of glucocorticoids on the brain. Data con-tinue to accumulate that indicate that high-doseglucocorticoid therapy is harmful for the devel-oping (prenatal and postnatal) brain. Further, Dr.New herself coauthored a paper reporting in-creased frequency of white matter abnormalitiesand temporal lobe atrophy on magnetic reso-nance imaging in patients with CAH. Althoughcause and effect remain to be established, onemust consider that glucocorticoid therapy mayhave played a role in causing these abnormalities(Frias et al. 2001, 805).

The AAP Committee concluded, in their responseto New:

The maxim of “first do no harm” requires a cau-tious, long-term approach, which is why the Acad-emy Committee unanimously agrees that prenatalglucocorticoid therapy for CAH should be con-fined to centers doing controlled prospective,long-term studies. The memory of the tragediesassociated with prenatal use of dexamethasoneand thalidomide demands no less (Frias et al.2001, 805, emphasis added).

A few months later, Pediatrics issued an erratum, cor-recting what may have been a Freudian slip; the AAPCommittee hadmeant to say “thememory of the tragediesassociatedwith the prenatal use of diethylstilbestrol (DES)

Bioethical Inquiry

and thalidomidedemandsno less” (Pediatrics2001, 1450,emphasis added).

Over the years, many individual researchers andclinicians expressed similar concerns about the use ofprenatal dexamethasone for CAH outside of appropriatestudies or, in some cases, about its use at all (Seckl andMiller 1997; Miller 1999; Ritzen 2001; Hughes 2003;Lajic et al. 2004; Hirvikoski et al. 2007). Even Forest,the French pioneer of the intervention, wrote in 2004,“the prenatal treatment of CAH remains an experimentaltherapy and, hence, must only be done with fully in-formed consent in controlled prospective trials approvedby human experimentation committees at centre’s thatsee enough of these patients to collect meaningful data”(2004, 479, emphasis added). By 2008, Walter Miller,distinguished professor of pediatrics and chief of endo-crinology at the University of California–San Francisco,declared, “It is this author’s opinion that this experimen-tal treatment is not warranted and should not be pursued,even in prospective clinical trials” (Miller 2008, 17).Miller later would add: “It seems to me that the mainpoint of prenatal therapy is to allay parental anxiety. Inthat construct, one must question the ethics of using thefetus as a reagent to treat the parent, especially when therisks are non-trivial” (in Dreger 2010, ¶20).

In spite of all these challenges and warnings, Newand her collaborators in the United States appear neverto have entered into a prospective, long-term, contin-uous study of the use of prenatal dexamethasone forCAH. New and her group do appear to have occasion-ally done some trials of prenatal dexamethasone dur-ing pregnancy, tracking outcomes up to the birth;among the 325 pregnancies included in studies seri-ously considered by the 2010 meta-analysis, 281 camefrom New’s group (Fernández-Balsells et al. 2010).Even those, however, were not studied in a matteradequate to establish efficacy or safety according tothe standards of evidence-based medicine. The trialslacked adequate controls and methods to mitigate bias.

Moreover, our recent FOIA findings on New’spregnancy trials of dexamethasone throw up multipleethical red flags. For example, in her 1985 applicationto the Cornell IRB to study prenatal dexamethasonefor CAH, New did not check the boxes indicating thather subject population included pregnant women andfetuses (New 1985, 2), even while, deeper in theapplication, she indicates that the study design callsfor administration of dexamethasone starting at two tofour weeks of gestation (New 1985, 9e). The

accompanying consent form describes this use as exper-imental, but then goes on to minimize the risks:

I understand that my participation in the projectinvolves the following risks: transient and revers-ible suppression of the maternal and fetal adrenalgland. For this reason, extra doses of steroids willbe administered to the mother at the time of deliv-ery to cover for the additional stress. Althoughcomplications of glucocorticoid therapy (cleft pal-ate, growth retardation, placental degenerationand fetal death) have been reported in laboratoryanimals, the doses used were extremely high.Congenital malformations associated with dexa-methasone therapy are rare in humans, even whenlarge doses are given. The pregnant women andfetuses treated to date with this regimen have notexperienced complications (New 1985, 9e).

Apregnantwomanreading thismight reasonablyhaveread “transient and reversible” to mean that the risksincluded no long-term harms to her or her offspring.

In another New York Presbyterian Hospital/CornellWeill Medical College consent form for the prenataladministration of dexamethasone for CAH, marked“IRB Approved” and dated April 2004, New requiredpregnant women to sign a form saying they under-stood the use was “experimental.” But the form alsoadvised the women: “Over the last decade, treatmentwith dexamethasone in the prescribed doses has beenshown to be effective in reducing the masculinizationof the female fetus with CAH and has been shown tobe safe for the fetus” (New 2004).

Thus, it remains unclear—but doubtful—whetherU.S. federal regulation 45 CFR 46 subpart B,which regulates experimentation on pregnant wom-en, was consistently followed in this use of prenataldexamethasone. Because the OHRP removed, fromits FOIA response to us, sections of its correspon-dence with Weill Cornell that might have indicatedhow many women were included in pregnancytrials of prenatal dexamethasone conducted byNew, we have been unable to determine how manyof the 600-plus pregnant women and fetuses shesays she had “treated” at Weill Cornell by 2003 hadthe benefit of IRB surveillance (such as it was).What we do know is that, given what we haveseen, even those engaged in IRB-approved trialsat Weill Cornell apparently cannot be said to havegiven informed consent.

Bioethical Inquiry

So far as we can ascertain, there has been and remainsan absence of IRB oversight for prenatal dexamethasoneadministration for CAH at Mount Sinai, where Newbegan working in June 2004, in spite of the fact thatNew has claimed the exposure of fetuses at Mount Sinaias evidence of her research progress there. For example,in her 2006 grant “progress report” to the NIH, Newindicated that she and her team had settled in at MountSinai and had been continuing the intervention there:“The prenatal diagnosis and treatment program has gal-loped ahead so that we now have diagnosed and ortreated 768 fetuses,” including 27 fetuses exposed todexamethasone from February 2005 to January 2006,i.e., when she was at Mount Sinai (New 2006, 3).

Our FOIA digging also turned up a 2004 letter fromJeffrey Silverstein, chair of the Mount Sinai IRB, assur-ing the NIH that New hadMount Sinai IRB approval fora project called “Prenatal Diagnosis and Treatment”(Silverstein 2004); the accompanying documents indi-cate that the project specifically involved the use ofprenatal dexamethasone for CAH. (New probably need-ed this IRB approval letter to continue her NIH fund-ing.) Yet in his 2010 response to the OHRP on behalf ofMount Sinai in response to our letters of concern, Silver-stein indicated that Mount Sinai did not believe IRBoversight of the decision to undertake this fetal inter-vention was needed, because New was not herself writ-ing the prescriptions (Silverstein et al. 2010).

Mount Sinai’s 2010 conclusions that New had notbeen doing research on those pregnancies appears to bebased on the confusing premise that other doctors hadbeen doing the prescribing to the pregnant womenwhose fetuses were then included in the growing numb-ers of New’s subjects. Perhaps Mount Sinai’s respond-ents to the OHRP in 2010 did not know that New hadbeen reporting statistics on fetal exposure as part of thefederally-funded research progress she described to theNIH as “gallop[ing] ahead” at Mount Sinai? But surelySilverstein, who lead-authored the Mount Sinai defensein 2010, should have known that he had himself assuredthe government in 2004 that New was intending prena-tal exposure as part of a study supposedly under IRBsupervision. If these fetuses were not regarded as re-search subjects locally in terms of having IRB protec-tions, they appear to have at least been counted asresearch subjects federally.

With Meyer-Bahlburg, New has also conducted afew follow-up studies, mostly low-quality questionnairestudies in which parents have been asked, long-distance,

to reply to a battery of questions. (The 2010 reviewfound these of such low quality, they did not even botherto consider them for the meta-analysis, and Meyer-Bahlburg has admitted that “fewer than 50% of mothersand offspring have responded to questionnaires”[Speiser et al. 2010b, under “3. Prenatal Treatment ofCAH”].) For these studies, the researchers had IRBapproval, but it does not appear that the families enrolledin these studies would have known that they might havebeen misled about the status of prenatal dexamethasonewhen it was administered to the pregnant women. Thusit is questionable whether their participation in thefollow-up study can be called fully informed.

So far as we can ascertain, New was not alone in herless-than-rigorous approach to scientific study of prena-tal dexamethasone for CAH. Indeed, although the inter-vention has been offered in many other nations, Swedenappears to be the only nation to have specifically re-stricted prenatal dexamethasone for CAH to womenwho agreed to participate in a continuous, prospective,long-term study of the intervention, a restriction insti-tuted there in 1999. (Before that it could be obtainedoutside of trials.) The group has been led by SvetlanaLajic, associate professor of molecular medicine andsurgery at the Karolinska University Hospital. In a re-cent exchange with one of us (Feder), Lajic revealed thatthe Swedish team has actually halted the interventionpart of the study due to concerns about adverse effects.

Lajic wrote to Feder that “due to our findingswe haveaddressed the Regional Ethics Committee in Stockholm,inNovember2010,andstatedthatdue topossibleadverseevents we wish to put on hold further recruitment ofpatients to the on-going prospective study of prenatalDEX treatment of CAH” (Lajic 2011). While our paperwas in press, the Swedish team published news of thisdevelopment, along with follow-up data on “43 childrentreated in Sweden and Norway during 1985–1995”(Hirvikoski et al. 2012, 1). When compared to controls,

[i]n general, treated children were born at termand were not small for gestational age. As agroup, they did not exhibit teratogenous effects/gross malformations, although eight severe ad-verse events were noted in the treated group,compared with one in the control group. Threechildren failed to thrive during the first year oflife; in addition, one had developmental delayand hypospadias; one had hydrocephalus; twogirls were born small for gestational age, and

Bioethical Inquiry

one of these girls was later diagnosed with men-tal retardation; and one child had severe moodfluctuations that caused hospital admission. Inthe control group, only one child was admittedbecause of Down’s syndrome (Hirvikoski et al.2012, 2).

The Swedish team has clearly been alarmed by theextraordinary number of serious medical problemsamong the small group of children treated prenatally.

As for the cognitive and behavioral outcomes, intheir most recent report the Swedish team acknowl-edged that “The small sample size, relatively highrefusal rate, and the retrospective study design limitedthe conclusiveness of the results” of their follow-up ofthe behavioral development in 40 Swedish childrentreated prenatally. Nevertheless, they could report that

[a]n adverse effect was observed in the form ofimpaired verbal working memory in CAH-unaffected short-term-treated cases [i.e., the chil-dren who were not the intended targets of theintervention]. The verbal working memory ca-pacity correlated with the children’s self-perception of difficulties in scholastic ability,another measure showing significantly lowerresults in CAH-unaffected, DEX-exposed chil-dren. These children also reported increased so-cial anxiety. In the studies on gender rolebehavior, we found indications of more neutralbehaviors in DEX-exposed boys (Hirvikoski etal. 2012, 2).

In other words, the boys appeared relatively lessmasculine—another unintended effect.

The Swedish team argued that “the[se] results causeconcern because no side effects should be tolerated inCAH-unaffected children who do not benefit from thetreatment per se” (Hirvikoski et al. 2012, 2). Indeed,the team concluded its 2012 report with as strongly aworded ethics statement as has ever been issued by ateam engaged in the use of prenatal dexamethasone forCAH: “We find it unacceptable that, globally, fetusesat risk for CAH are still treated prenatally with DEXwithout follow-up” (Hirvikoski et al. 2012, 2).

As we urged United States governmental agenciesin 2010, the Swedish team now “urge[s] the scientificcommunity to perform additional retrospective stud-ies, preferably on all treated children and youngadults” (Hirvikoski et al. 2012, 2). Yet we see no signsthat rigorous, independently-audited, retrospective

studies will be pursued in the United States, wherethe great majority of interventions appear to haveoccurred, largely under the guidance of Maria New.Although we find plenty of suggestions in New’s grantmaterials and presentations that results from her retro-spective follow-up studies are forthcoming, and al-though the NIH repeatedly renewed her prenataldexamethasone research funding, little appears to havebeen produced in terms of longer-term data on prenataldexamethasone for CAH, particularly with regard tolong-term safety. We can find no publications resultingfrom New’s 2007 Rare Diseases Clinical ResearchNetwork (RDCRN/NIH) follow-up study protocol,except a paper she co-authored in a 2011 issue ofAdvances in Experimental Medicine and Biology. Thispaper purports to demonstrate the long-term safety ofprenatal dexamethasone for CAH. But the article con-tains no methods section, no description of the studyallegedly being reported, no description of the con-trols, nor even of the intervention. It consists simply ofunexplained tables of data and unsupported narrative(New and Parsa 2011). Needless to say, it is not thekind of report that will ever make it into a meta-analysis.

Although New had told the U.S. government in1996 “we propose to continue our studies of prenataldiagnosis and treatment” (New 1996b, 61), we canfind no evidence of there ever having been, in theUnited States, a reasonably-designed, IRB-approved,prospective, long-term study—nothing like the rigor-ous approach taken in Sweden. In a recent debate withDreger on this subject, Meyer-Bahlburg confirmed thetotal absence of prospective continuous studies in theUnited States and offered no indication that any hasever even been planned (Meyer-Bahlburg 2011). Thisis very concerning, and is even more worrisome whenone considers the design of New’s 2007 RDCRN/NIHretrospective follow-up study (to be carried out withMeyer-Bahlburg). As we discovered from our FOIArequests, that protocol specifically states as an “exclu-sion criteria for all groups” this: “mental impairmentwhich prevents understanding of questionnaire” (New2007, 25).

So, while the researchers in Sweden are document-ing cognitive impairment among those exposed toprenatal dexamethasone for CAH, researchers inAmerica have specifically designed a follow-up studythat prevents detection of certain negative effects oncognitive development.

Bioethical Inquiry

Promotion of Prenatal Dexamethasone for CAH

New has a clear track record of promoting the use ofprenatal dexamethasone for CAH as safe and effectiveto clinicians who might reasonably have expected herto represent accurately to them what was actuallyknown and unknown. In a co-authored article for the2000 edition of the Cecil Textbook of Medicine, Newadvised her colleagues: “Prenatal treatment with dexa-methasone has been shown to be safe and effective forboth mother and child in the largest human studies”(New and Josso 2000, 1302), implying that there werelarge human studies of sufficiently high quality toestablish safety and efficacy. A few years later, New’sdiscussion of prenatal dexamethasone (published withtwo co-authors) in the 2007 edition of the textbookPediatric Endocrinology reads, “we believe that prop-er prenatal treatment of fetuses at risk for CAH can beconsidered effective and safe. Long-term studies onthe psychological development of patients treated pre-natally are currently underway”—a tacit admission ofmore interest in outcomes related to gender identityand cognitive development than in metabolic out-comes like those involving cardiovascular function(New, Ghizzoni, and Lin-Su 2007, 237).

New’s determined influence on prenatal treatmentpractices for CAH is also illustrated by the work shehas published in GeneReviews, the NIH-sponsoredfree online textbook regarded as an authoritativesource in prenatal counseling. Until recently (for rea-sons we explain below), New’s article described pre-natal dexamethasone for CAH as if it were standardpractice, explaining precisely how clinicians in thefield could implement the intervention. No mentionwas made of its experimental status, of the fact that theuse is off-label, nor of the absence of evidence for itsefficacy and safety (Nimkarn and New 2009; cf.Witchel and Miller 2012).

In her grants with the NIH, New also representedprenatal dexamethasone for CAH as having beenshown safe and effective. For example, in her 2003report, she indicated: “Based on our experience andother large human studies, proper prenatal diagnosisand treatment of 21-OHD is safe for mother and child,and is effective” (New 2003a, 98). In her NIH grantmaterials, New used the fact that “[w]e are the onlygroup in the U.S.A. routinely carrying out prenataldiagnosis and treatment of CAH” as a major reasonwhy the government should fund her studies on the

“large population of prenatally-treated infants” shehad “accumulated” (New 1996b, 2). Already by her1996 report to the NIH, New was claiming her clinic“receive[d] requests [for the intervention] from allover the U.S. and foreign countries at the rate of 3–4per week” (New 1996b, 61). A decade later, New’sprotocol for a follow-up study again indicated that herclinic had been drawing patients from all over theUnited States (New 2007, 25–26); recall that by2006 she reported use of the intervention in 768 preg-nancies (New 2006, 3).

The large draw of potential subjects for her grantsperhaps occurred because New actively promoted pre-natal dexamethasone for CAH as safe and effective notonly to clinicians but also directly to parents, includingthrough the CARES Foundation, a non-profit organi-zation dedicated to supporting individuals and familieswith CAH and to advancing research and improvedclinical practices (e.g., newborn screening). New’s2001 lecture to parents at CARES, quoted above,represents one example. Another appears in theCARES Foundation Winter 2003 newsletter, forwhich Elizabeth Kitzinger of Weill Cornell MedicalCollege provided a short article effectively advertisingNew’s clinic as the place to go for at-risk mothers:

In the United States, the only center routinelyoffering prenatal diagnosis and treatment is Dr.Maria New’s clinic at New York PresbyterianHospital-Weill Medical Center (Cornell) inNew York City. Dr. New has treated over 600pregnant women at risk for the birth of a CAH-affected child.… The results are remarkable. Dr.New maintains contact with all children treatedprenatally, and has found no adverse develop-mental consequences. Thus, with nearly20 years’ experience, the treatment appears tobe safe for mother and child, though there areendocrinologists who are wary of using dexa-methasone prenatally even now (Kitzinger 2003,¶2–¶3).

Some parents reading this might hear in that lastline a warning that not all clinicians were convincedthis use was safe and effective. But others mightreasonably read it as an indication that Dr. New wouldbe the only clinician willing to help them. The textcontinues:

It is important to note that prenatal diagnosis andtreatment should ONLY be done in a clinic like

Bioethical Inquiry

Dr.New’swith longexperienceandcommitment tofollow-up. Only by tracking the growth of prena-tally treated children can the long-term effects oftreatment be exhaustively studied. Administeringdexamethasone to achieve normal genitaliarequires the judgmentandexperienceofspecialists.The benefits to families of classically affected girlscannot be underestimated. We hope that the avail-ability of this treatment will be shared with allfamilies at risk for the birth of CAH-affected chil-dren. (Kitzinger 2003, ¶4, capitalization original).

Even since the 2010meta-analysis, the website of theMaria New Children’s Hormone Foundation continuesto claim “the treatment has been found safe for motherand child” (New 2010a, ¶4). In 2010, our complaints tothe FDA about advertisement of this off-label use as“safe for mother and child” were referred to Robert“Skip” Nelson, an FDA-based pediatrician and ethicist.As mentioned above, our discussions with Nelson clar-ified that regulations prohibit only two groups fromadvertising off-label uses as “safe and effective”:employees of a drug’s maker (which New is not) andFDA-approved investigators of drugs.

According to Nelson, New did seek and obtain anIND (investigational new drug) exemption from theFDA in 1996 for prenatal dexamethasone for CAH; thiswould mean she sought and obtained the FDA’s permis-sion at that time for a specific study of this drug use. Butas Nelson explained to us, since New does not currentlyhave an approval from the FDA to study prenatal dexa-methasone, she does not count as an FDA investigator,so she is not currently prohibited from calling thisintervention “safe and effective.” In other words, be-cause of a regulatory loophole in the United States, ifyou inappropriately investigate an off-label use of adrug, then you can also inappropriately advertise it—even to pregnant women and even when the drug use ismeant to alter the course of fetal development.

Notably, we think Nelson may be incorrect in hisclaim that in 1996 the FDA granted New an IND ex-emption for the use of prenatal dexamethasone to pre-vent sex atypicality in CAH. Through the FOIA, weobtained the 1996 FDA letter cited by Nelson in 2010,and it actually refers only to a “proposal to utilizedexamethasone to treat pregnant women with a [sic]congenital adrenal hyperplasia” (Sobel 1996). It is en-tirely possible the 1996 letter referred to a study of theuse of dexamethasone to treat women with CAH whobecame pregnant, i.e., an off-label use meant to treat a

woman herself afflicted with CAH to keep her healthyduring her pregnancy, an entirely different medical mat-ter than an explicit attempt at fetal engineering whereinthe mother is merely a carrier of CAH. There appears tobe no evidence to support Nelson’s representation of the1996 IND exemption letter.

AWorrisome Track Record

We feel optimistic that our efforts to draw attention tothis use of prenatal dexamethasone have increased thelikelihood that physicians and researchers will respectthe rights of the population exposed. Nevertheless, wefeel pessimistic about ever knowing what really hap-pened to most of those already exposed—for weeks ormonths of pregnancy or fetal development. Recall thatin 2002 a joint statement by the European and Amer-ican pediatric endocrinology societies called for dataon prenatal dexamethasone outcomes to be enteredinto “a central database audited by an independentsafety committee” (Joint LWPES/ESPE CAH Work-ing Group 2002, 4049). But—except for a still unpub-lished European study known as “PREDEX,” whichenrolled only 24 subjects from 1999 to 2004, includ-ing subjects from the Swedish prospective cohort(Lajic et al. 2004)—no such thing has happened. In-stead, it appears from the 2007 RDCRN/NIH studyprotocol that Maria New retains control of the data-base of contact information for what she reports isnow more than 768 children and their mothers whohave been exposed to this prenatal interventionthrough her clinics (New 2006, 3). It seems likely thatthat population represents at least a significant minor-ity of those exposed. In fact, New’s 2001 NIH “appli-cation for continuation grant” provides a tabledescribing human subjects under the “specific [study]aim” called “prenatal dx and treatment in families atrisk,” and there the total number of subjects is stated as2,144 (New 2001b, 14).

Our research has caused us substantial concernabout what appears to be a pattern of misrepresenta-tion by Maria New, even beyond what we take to bemisrepresentations regarding the status of prenataldexamethasone for CAH. As reported in The WallStreet Journal in 2005, one of New’s NIH grants(which included work on CAH) formed the subjectof a fraud suit brought against Weill Cornell MedicalCollege—a suit over “phantom studies” that resulted

Bioethical Inquiry

in a settlement whereby Cornell paid the government$4.4 million (Wysocki 2005). While the settlementrequired no admission of wrongdoing, it seems signif-icant that, at the time of the fraud case, New’s status atCornell radically changed; substantial portions of herCornell titles and salary appear to have been adminis-tratively withdrawn.2

An oblique exchange in which we participated in2010 raises additional concerns about New’s trackrecord for trustworthiness. In a project aimed at mak-ing known the experimental status of prenatal dexa-methasone for CAH, Dreger wrote with Taylor Sale(Dreger’s student and a genetic counselor) to the edi-tors of GeneReviews to request that Dr. New’s articlein that publication be changed to reflect medical con-sensuses concerning prescription of prenatal dexa-methasone for CAH (Dreger and Sale 2010). Theeditors reviewed the consensus statements Dregerand Sale provided them and then wrote to New withrecommended changes. Some time later, one of theeditors wrote to Dreger and Sale to report that: “Dr.New’s initial reply to our proposed edits to the 21-hydroxylase deficient [sic] CAH GeneReview is that‘Prenatal dexamethasone treatment has been FDA ap-proved by Dr. Sobel.’” The editor added, “We areinterested in your thoughts on [Dr. New’s] comment”(Dolan 2010). We informed the editors that SolomonSobel was the FDA physician who had signed off in1996 on a single IND exemption (Sobel 1996). As wesurely did not need to explain to the GeneReviewseditors, this did not qualify prenatal dexamethasonefor CAH as “FDA approved.”

Today, New’s co-authored GeneReviews article on21-OHD CAH says this: “Prenatal treatment shouldcontinue to be considered experimental and shouldonly be used within the context of a formal IRB-

approved clinical trial” (Nimkarn and New 2010b, ¶1under “Therapies Under Investigation”). Since the2010 revision, the article no longer provides detailedinstructions on how to conduct the intervention. Andyet, the change reflected in the GeneReviews articledoes not appear to mark a major change in approachfor New. Just after the revision of the GeneReviewspiece, New published a short article in The AmericanJournal of Bioethics entitled, “Vindication of PrenatalDiagnosis and Treatment of Congenital Adrenal Hy-perplasia with Low-Dose Dexamethasone.” There shewrote: “The recent reports by the Office of HumanResearch Protections and the FDA … make crystalclear that my research on prenatal treatment of CAH isand always has been both legally and ethically properat every level” (New 2010c, 68).

In spite of our petitions, the Office of Human Re-search Protections (OHRP) appears to be quite a bitless concerned than we are about the veracity of New’sclaims. For example, the agency appears to have ac-cepted a claim that New had not been conducting fetalexperimentation with dexamethasone at Mount Sinai,apparently without learning or considering that her2006 NIH grant report described “gallop[ing] ahead”with the intervention and specified, as part of her“research progress report,” at least 27 fetuses exposedto prenatal dexamethasone for CAH since New hadrelocated her clinic to Mount Sinai (New 2006). Aspart of its investigation following our letters, theOHRP uncovered the deeply problematic IRB-approved consent forms from Weill Cornell mentionedabove, yet the OHRP accepted New’s claims thatappropriate IRB oversight and informed consent hadoccurred. The OHRP staff did not indicate in theirresponse to us how many of the pregnant womenNew claims to have “treated” were even in IRB-approved trials, nor did they address the problematicdisjuncture between her own advertisement of prenataldexamethasone as “safe for mother and child” and hersimultaneous federally funded study to investigatewhether in fact it is safe for mother and child.

This all seems particularly strange since Tamar-Mattis’s research turned up two strongly-worded2004 determination letters from the OHRP findingmajor faults with New’s IRB-approved studies at WeillCornell (Tamar-Mattis 2010). (OHRP determinationletters are the final result of investigations that revealproblems in the conduct of research.) New was not theonly researcher at Cornell named in the findings; in

2 On February 12, 2003, New wrote to the NIH asking formoney to support herself, under the NIH Merit Award system:“As I am no longer Chairman of Pediatrics, Chief of PediatricEndocrinology, and Program Director of the CCRC, I havemuch more time to devote to the research proposed in my MeritAward. … This is a hard time for me and I am deeply apprecia-tive of your consideration” (New 2003b). In a subsequent inter-nal memo, the NIH staff “enthusiastically support[ed]” givingNew more money under the Merit Award system, without men-tioning why “her circumstances changed abruptly this year whenshe had to relinquish the chairmanship of the Department ofPediatrics and the directorship of the Children’s Clinical Re-search Center at Weill-Cornell Medical School and the salariesentailed in these positions” (NIH Staff 2003). Shortly after, Newwas hired by Mount Sinai School of Medicine.

Bioethical Inquiry

fact, the OHRP found the entire system for reviewingpediatric research at Cornell so problematic that theyplaced a restriction on Cornell’s Federalwide Assur-ance and took the extraordinary step of requiring re-view by the IRB of all active research involvingchildren (McNeilly 2004). The problems the OHRPfound with protection for subjects in New’s studieswere particularly alarming: an informed consent formthat did not include a description of the purpose ofresearch, as required (McNeilly 2004, 5); consentforms that contained extremely complex language thata subject would be unlikely to understand (McNeilly2004, 6); an informed consent form that did not statethat “the tests conducted for the protocol could beobtained outside the research” (McNeilly 2004, 5);“subjects enrolled outside the protocol age range priorto IRB review and approval” (McNeilly 2004, 4);missing IRB records (McNeilly 2004, 3) and researchinitiated without first obtaining legally informed con-sent (McNeilly 2004, 3). The OHRP also noted thatWeill Cornell had suspended New’s research protocolin the fall of 2002 but did not report the suspension tothe OHRP until June 2003 (McNeilly 2004, 4).

Why so much scrutiny of New and Weill Cornell bythe OHRP in 2004 and so little by the OHRP in 2010?This seems to be part of a problematic trend forming atthe OHRP—again suggesting that prenatal dexametha-sone for CAH is not a unique case but a bellwether. AMarch 2011 analysis from the Report on ResearchCompliance on the OHRP has found a substantialdrop-off of OHRP determination letters in the lastfour years: “Agency observers and others expressedconcern about the steep drops in letters and open cases,telling [the Report on Research Compliance] they raisequestions about the agency’s current commitment toserious oversight of human subjects research and inves-tigations into possible wrongdoing” (National Councilof University Research Administrators 2011, 1). Nota-bly, the “possibility that compliance is increasing atinstitutions was not among the reasons OHRP cited forthe drop, and funding is not a problem” (National Coun-cil of University Research Administrators 2011, 1). Norhas the number of complaints made to the OHRP fallen.

Final Thoughts

The OHRP and FDA have not yet fully responded to ourFOIA requests. (Dreger is presently suing to obtain the

remainder of the documents.) But even what we alreadyhave found indicates that the government could wellhave made a case for inappropriate behaviors here andcould have issued statements echoing at least some ofour concerns about the way that prenatal dexamethasonefor CAH has been administered and studied.

Despite the disappointing responses from the OHRPand FDA, we do not regret raising the alarm as we didstarting in January 2010. Doing so increased awarenessamong the affected population about the actual status ofprenatal dexamethasone and has also shone light intocorners we would not otherwise be able to view. Forexample, it made available to the public New’s retro-spective study protocol and IRB-approved consentforms, and it also led to a reporter for Time magazinefinding women who indicated that they did not know,when given prenatal dexamethasone to attempt preven-tion of virilization in female fetuses, that it was an off-label and controversial drug use (Elton 2010). Withoutthe investigation, this valuable information would haveremained hidden from view.

The investigation also seems to have driven MountSinai to take action, judging from Silverstein’s re-sponse to the OHRP:

The Committee [at Mount Sinai charged withresponding] determined that there are widely dif-fering opinions amongst the staff, with some staffmembers expressing significant concerns regard-ing the use of dexamethasone for the prenataltreatment of CAH. A particular concern is thecurrent necessity to treat potentially unaffectedfetuses until a diagnosis is determined. Therefore,the Committee concluded that the clinical use ofdexamethasone in this situation should require arigorous informed consent process with detaileddocumentation that the risks and benefits of thistreatment have been clearly communicated to theparents making a decision to engage in prenataltreatment. The Committee also recommends thatthis issue be referred to the Medical Board of TheMount Sinai Hospital for further consideration ofthe consent issue. (Silverstein et al. 2010, 11).

It would appear, then, that Mount Sinai now sharesour concerns about the practices associated with theadministration of dexamethasone. Nevertheless, it isstill the case that the Maria New Children’s HormoneFoundation website declares that prenatal dexametha-sone for CAH “has been found safe for mother and

Bioethical Inquiry

child” and provides a phone number to call to make anappointment (New 2010a, ¶4). When the number iscalled, it rings to a clinic at Mount Sinai.

Epilogue

As our paper was in press, Maria New’s research group,led by Meyer-Bahlburg, published a study includingsome cognitive outcome data for 67 children prenatallyexposed to dexamethasone for CAH (Meyer-Bahlburg etal. 2012). The children studied came from New’s data-base (Meyer-Bahlburg et al. 2012, line 92) and includedeight CAH-affected girls whowere “long-term” exposedin utero and 59 boys andCAH-unaffected girlswhowere“short-term” exposed (Meyer-Bahlburg et al. 2012, line23). These children were compared to 73 unexposedcontrols (Meyer-Bahlburg et al. 2012, line 24).

The new paper concludes: “Our studies do not repli-cate a previously reported adverse effect of short-termprenatal DEX exposure on working memory, while ourfindings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about poten-tially adverse cognitive aftereffects of such exposure”(Meyer-Bahlburg et al. 2012, lines 34–36). The “previ-ously reported adverse effect of short-term prenatalDEX exposure” was that reported by the Swedish team(Hirvikoski et al. 2007). But whereas the Swedish teamemployed a relatively rigorous design (a prospective,controlled, long-term study), in the new study fromNew’s group, the 67 exposed children were selectedvia convenience sampling performed retrospectively.

Furthermore, although the new Meyer-Bahlburg etal. publication purports to seek information on theeffects of dexamethasone exposure (Meyer-Bahlburget al. 2012, lines 26–27), among the eight girls long-term exposed the degree of exposure varies from a totalof nine weeks of fetal life to a total of 39 weeks (Meyer-Bahlburg et al. 2012, lines 117–120), an exposure-length difference of more than four times, making itvery difficult to establish meaningful dose-effect.

In marked contrast to the Swedish team, and as if toconfirm the weakness of the study by New’s group,Meyer-Bahlburg et al. found some “positive” cognitiveoutcomes in the short-term treated children. Understand-ably, they found this hard to explain. (No one suspectsfirst-trimester glucocorticoid exposure at 60 to100 timesnormal levels to be good for children’s brains.) In theirdiscussion, the authors try to explain the lack of

corroboration of their results by other studies or by logic(Meyer-Bahlburg et al. 2012, lines 278–298), but they donot propose the most obvious explanation for this verystrange finding: The paper’s study population is a highlyskewed sample.

We document here that New has claimed to have“treated” somewherebetween600and2,144 fetuseswithdexamethasone for CAH, yet her group is now reportingcognitive outcomes ononly67children in her database, atiny fraction of thosewho ought to be available for study.Furthermore, based on New’s claims to the public and toher granting agencies, her efforts should have producedbetween about 98 and 268 girls who were long-termdexamethasone-exposed, yet here her group reports oncognitive outcomes in only eight. Thus it would appearthat the children included in the new study fromMeyer-Bahlburg et al. represent somewhere between only 3 and12 percent of the population prenatally exposed to dexa-methasone under New’s consultation.

What the new paper from Meyer-Bahlburg et al.actually appears to replicate is our finding: that theapproach taken byNew and her collaborators to prenataldexamethasone for CAH has been so scientifically weakas to be both clinically uninformative and profoundlyunethical, especially in light of the history of DES.

Acknowledgments The authors thank Heather Appelbaum,J.J. Burchman, James A. Bruce, Joel Frader, Susan Gilbert,Janet Green, Philip Gruppuso, Mary Ann Harrell, ShelleyHarshe, Hilde Lindemann, Johanna Michael, Thad Morgan,Robert Nelson, Nigel Paneth, Taylor Sale, David Sandberg,Aron Sousa, Valerie Thonger, Kiira Triea, Katie Watson, EricVilain, two anonymous reviewers, and the journal’s editors forassistance with this work. Funding for this project has beenprovided to Alice Dreger by the Office of the Provost of North-western University.

Open Access This article is distributed under the terms of theCreative Commons Attribution License which permits any use,distribution, and reproduction in any medium, provided theoriginal author(s) and the source are credited.

References

Borror, K.C. 2010. Concerning activities conducted by Dr.Maria New at Weill Cornell Medical College (WCMC)and Mount Sinai School of Medicine (MSSM). Letter toE.K. Feder and A. Dreger, September 2.

Crouch, N.S., C.L. Minto, L.M. Laio, C.R. Woodhouse, andS.M. Creighton. 2004. Genital sensation after feminizinggenitoplasty for congenital adrenal hyperplasia: A pilotstudy. BJU International 93(1): 135–138.

Bioethical Inquiry

David, M., and M.G. Forest. 1984. Prenatal treatment of con-genital adrenal hyperplasia resulting from 21-hydroxylasedeficiency. The Journal of Pediatrics 105(5): 799–803.

Dessens, A.B., F.M. Slijper, and S.L. Drop. 2005. Gender dys-phoria and gender change in chromosomal females withcongenital adrenal hyperplasia. Archives of Sexual Behav-ior 34(4): 389–397.

Devaney, S.A., G.E. Palomaki, J.A. Scott, and D.W. Bianchi.2011. Noninvasive fetal sex determination using cell-freefetal DNA: A systematic review and meta-analysis. JAMA306(6): 627–636.

Dolan, C. 2010. Re: GeneReview correction. E-mail to A.Dreger, July 16.

Dreger, A. 2010. Issue: Reasonable experiment? fetaldex.org.http://www.fetaldex.org/experimentation.html.

Dreger,A.,andT.Sale.2010.RegardingS.NimkarnandM.I.New’s“21Hydroxylase-DeficientCongenitalAdrenalHyperplasia.”Letter toGeneReviews editor C.R. Dolan, June 29.

Dreger, A., E.K. Feder, and A. Tamar-Mattis. 2010. Preventinghomosexuality (and uppity women) in the womb? Bioeth-ics Forum, June 29. http://www.thehastingscenter.org/ Bio-ethicsforum/Post.aspx?id04754.

Dreger, A.D., N. Paneth, J. Frader, P. Gruppuso, and E.K. Feder.Forthcoming. Lessons not learned from DES? The case ofprenatal dexamethasone for CAH.

Dresser, R., and J. Frader. 2009. Off-label prescribing: A call forheightened professional and government oversight. TheJournal of Law, Medicine and Ethics 37(3): 476–486, 396.

Eder, S. 2011. The birth of gender: Clinical encounters withhermaphroditic children at Johns Hopkins (1940–1956).Ph.D. diss., The Johns Hopkins University.

Elton, C. 2010. A prenatal treatment raises questions of medicalethics. Time, June 18. http://www.time.com/time/health/article/0,8599,1996453,00.html.

Fernández-Balsells, M.M., K. Muthusamy, G. Smushkin, et al.2010. Prenatal dexamethasone use for the prevention ofvirilization in pregnancies at risk for classical congenitaladrenal hyperplasia because of 21-hydroxylase (CYP21A2)deficiency: A systematic review and meta-analyses. ClinicalEndocrinology 73(4): 436–444.

Forest, M.G. 2004. Recent advances in the diagnosis and manage-ment of congenital adrenal hyperplasia due to 21-hydroxylasedeficiency. Human Reproduction Update 10(6): 469–485.

Frias, J., L.S. Levine, S.E. Oberfield, S. Pang, and J. Silverstein(for the AAP Ad Hoc Writing Committee). 2001. In replyto “Prenatal treatment of Congenital Adrenal Hyperplasia:author differs with technical report” by M.I. New. Pediat-rics 107(4): 805.

Goodman, A., J. Schorge, and M.F. Greene. 2011. The long-term effects of in utero exposures—the DES story. TheNew England Journal of Medicine 364(22): 2083–2084.

Herbst, A.L., H. Ulfelder, and D.C. Poskanzer. 1971. Adeno-carcinoma of the vagina. Association of maternal stilbestroltherapy with tumor appearance in young women. The NewEngland Journal of Medicine 284(15): 878–881.

Hirvikoski, T., A. Nordenström, T. Lindholm, et al. 2007. Cogni-tive functions in children at risk for congenital adrenal hy-perplasia treated prenatally with dexamethasone. The Journalof Clinical Endocrinology and Metabolism 92(2): 542–548.

Hirvikoski, T., A. Nordenström, A. Wedell, M. Ritzén, and S.Lajic. 2012. Prenatal dexamethasone treatment of children

at risk for congenital adrenal hyperplasia: The Swedishexperience and standpoint. The Journal of Clinical Endo-crinology and Metabolism 97(6). doi:10.1210/jc.2012-1222.

Hughes, I.A. 2003. Management of fetal endocrine disorders.Growth Hormone and IGF Research 13(Supplement A):S55–S61.

Joint LWPES/ESPE CAH Working Group. 2002. Consensusstatement on 21-hydroxylase deficiency from the LawsonWilkins Pediatric Endocrine Society and the EuropeanSociety for Paediatric Endocrinology. The Journal of Clin-ical Endocrinology and Metabolism 87(9): 4048–4053.

Kitzinger, E. 2003. Prenatal diagnosis & treatment for classicalCAH. CARES Foundation Newsletter 2(1): 15. http://www.caresfoundation.org/productcart/pc/news_letter/ win-ter02-03_page_9.htm.

Lajic, S. 2011. Re: Question about your study of dexametha-sone. E-mail to E.K. Feder, September 19.

Lajic, S., A. Wedell, T.H. Bui, E.M. Ritzén, and M. Holst. 1998.Long-term somatic follow-up of prenatally treated childrenwith congenital adrenal hyperplasia. The Journal of Clini-cal Endocrinology and Metabolism 83(11): 3872–3880.

Lajic, S., A. Nordenström, E.M. Ritzén, and A. Wedell. 2004.Prenatal treatment of congenital adrenal hyperplasia. Euro-pean Journal of Endocrinology/European Federation ofEndocrine Societies 151(Supplement 3): U63–U69.

Lajic, S., A. Nordenström, and T. Hirvikoski. 2011. Long-termoutcome of prenatal dexamethasone treatment of 21-hydroxylase deficiency. Endocrine Development 20: 96–105.

Lee, P.A., and C.P. Houk. 2010. Review of outcome informationin 46, XX patients with congenital adrenal hyperplasiaassigned/reared male: What does it say about gender as-signment? International Journal of Pediatric Endocrinol-ogy 2010: 982025. doi:10.1155/2010/982025.

Lee, P.A., C.P. Houk, S.F. Ahmed, and I.A. Hughes. 2006.Consensus statement on management of intersex disorders.International Consensus Conference on Intersex. Pediat-rics 118(2): e488–e500.

Marciniak, B., J. Patro-Malysza, E. Poniedziałek-Czajkowska,Z. Kimber-Trojnar, B. Leszczyńska-Gorzelak, and J.Oleszczuk. 2011. Glucocorticoids in pregnancy. CurrentPharmaceutical Biotechnology 12(5): 750–757.

McNeilly, P.J. (for the Office for Human Research Protections).2004. Re: Human research subject protections underMultipleProject Assurance (MPA) M-1185 and Federalwide Assur-ance (FWA) 93. Letter to A.M. Grotto and J.M.Cohen, WeillCollege of Medicine of Cornell University, July 21.

Meyer-Bahlburg, H.F. 1999. What causes low rates of child-bearing in congenital adrenal hyperplasia? The Journal ofClinical Endocrinology and Metabolism 84(6): 1844–1847.

Meyer-Bahlburg, H.F. 2011. Debate in sexology: Prenatal dexa-methasone treatment of pregnancies at risk of offspringwith Congenital Adrenal Hyperplasia (CAH). Paper pre-sented at the conference for the International Academy ofSex Research, August 10–14, Los Angeles, CA.

Meyer-Bahlburg, H.F., C. Dolezal, S.W. Baker, A.A. Ehrhardt,and M.I. New. 2006. Gender development in women withcongenital adrenal hyperplasia as a function of disorderseverity. Archives of Sexual Behavior 35(6): 667–684.

Meyer-Bahlburg, H.F.L., C. Dolezal, R. Haggerty, M. Silverman,and M.I. New. 2012. Cognitive outcome of offspring from

Bioethical Inquiry

dexamethasone-treated pregnancies at risk for congenitaladrenal hyperplasia due to 21-hydroxylase deficiency. Euro-pean Journal of Endocrinology, May 1. Epub ahead of print.doi:10.1530/EJE-11-0789.

Miller, W.L. 1999. Dexamethasone treatment of congenital ad-renal hyperplasia in utero: An experimental therapy ofunproven safety. The Journal of Urology 162(2): 537–540.

Miller, W.L. 2008. Prenatal treatment of classic CAH with dexa-methasone: Pro vs. con. Endocrine News (Tri-Point Series),April: 16–18. http://www.endo-society.org/endo_news/tri_point/2008/upload/CAH-Bi-Point-Part-1.pdf and http://www.endo-society.org/endo_news/tri_point/2008/upload/CAH-Bi-Point-Part-2.pdf.

Murphy, T.M. 1997. Gay science: The ethics of sexual orienta-tion research. New York: Columbia University Press.

National Council of University Research Administrators. 2011.Big drop in OHRP letters, open cases raise questions ofagency commitment. Report on Research Compliance 8(3):1–3. http://www.reportonresearchcompliance.com/rrc0311_reprint.pdf.

New, M.I. 1985. IRB application (approved) for project entitled“Steroid 21-Hydroxylase Deficiency: Inborn error of ste-roid synthesis.” New York: New York Hospital-CornellMedical Center Institutional Review Board.

New, M.I. 1996a. Androgen metabolism in childhood. Grantapplication R01 HD00072-33 (approved). National Institutesof Health. New York: Cornell University Medical College.

New,M.I. 1996b. Androgenmetabolism in childhood. Grant appli-cationR01HD00072-33A1 (approved). National Institutes ofHealth. NewYork: Cornell UniversityMedical College.

New, M.I. 2001a. Lecture on prenatal dexamethasone to parents.Paper presented at the conference for the CARES Founda-tion, November 14, Weill Medical College of Cornell Uni-versity, New York, NY.

New, M.I. 2001b. Application for continuation grant entitled “An-drogen metabolism in childhood.” Grant 5-R37-HD00072-37(approved). National Institute of Child Health and HumanDevelopment. New York: Weill Cornell Medical College.

New, M.I. 2003a. Natural history of rare genetic steroid disor-ders. Grant application U54 RR019484-01 (approved). Na-tional Center for Research Resources. New York: WeillCornell Medical College of Cornell University.

New, M.I. 2003b. Re: 4-R37HD00072-38. Letter to N.D.Alexander, February 12.

New, M.I. 2004. Consent form for clinical investigation (IRBapproved) for project entitled “Hypo- and hyperadrenalstates/prenatal diagnosis and therapy.” New York: NewYork Presbyterian Hospital-Weill Medical College of Cor-nell University.

New, M.I. 2006. Androgen metabolism in childhood. Grantprogress report 5-R37-HD00072-42. Department of Healthand Human Services, Public Health Services. New York:Mount Sinai School of Medicine.

New, M.I. 2007. Long-term outcome in offspring and mothers ofdexamethasone-treated pregnancies at risk for classical Con-genital Adrenal Hyperplasia owing to 21-hydroxylase defi-ciency. Rare Diseases Clinical Research Network (researchprotocol). New York: Mount Sinai School of Medicine.

New, M.I. 2010a. Prenatal diagnosis and treatment of congenitaladrenal hyperplasia. The Maria New Children’s HormoneFoundation. http://www.newchf.org/testing.php.

New, M.I. 2010b. Long Range Outcome of Prenatal Treatment.Paper presented at the Second World Conference, Hormonaland Genetic Basis of Sexual Differentiation Disorders andHot Topics in Endocrinology, January 15, Miami Beach, FL.

New, M.I. 2010c. Vindication of prenatal diagnosis and treatmentof congenital adrenal hyperplasia with low-dose dexametha-sone. The American Journal of Bioethics 10(12): 67–68.

New, M.I., A. Carlson, J. Obeid, et al. 2001. Extensive personalexperience: Prenatal diagnosis for congenital adrenal hy-perplasia in 532 pregnancies. The Journal of Clinical En-docrinology and Metabolism 86(12): 5651–5657.

New,M.I.,L.Ghizzoni,andK.Lin-Su.2007.Anupdateofcongenitaladrenal hyperplasia. InPediatric endocrinology, 5th edition, ed.F. Lifshitz, 227–245. NewYork: InformaHealthcare.

New,M.I., andN. Josso. 2000.Disorders of sexual differentiation. InCecil textbookofmedicine,21stedition,ed.L.GoldmanandJ.C.Bennett, 1297–1306. Philadelphia:W.B. Saunders Company.

New, M.I., and A.A. Parsa. 2011. Long range outcome ofprenatal treatment. Advances in Experimental Medicineand Biology 707(Part 2): 33–35.

NIH Staff. 2003. Administrative increase/administrative supple-ment, staff recommendation (re. Maria I. New). Bethesda,MD: National Institutes of Health, April 3, April 4, April 7.

Nimkarn, S., and M.I. New. 2007. Prenatal diagnosis and treat-ment of congenital adrenal hyperplasia. Hormone Research67(2): 53–60.

Nimkarn, S., and M.I. New. 2009. 21-Hydroxylase-DeficientCongenital Adrenal Hyperplasia. In GeneReviews, ed.R.A. Pagon, T.D. Bird, C.R. Dolan, et al. Seattle: Univer-sity of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK1171/.

Nimkarn, S., and M.I. New. 2010a. Congenital adrenal hyper-plasia due to 21-hydroxylase deficiency: A paradigm forprenatal diagnosis and treatment. Annals of the New YorkAcademy of Sciences 1192: 5–11.

Nimkarn, S., and M.I. New. 2010b. 21-Hydroxylase-DeficientCongenital Adrenal Hyperplasia (revised from 2002). InGeneReviews, ed. R.A. Pagon, T.D. Bird, C.R. Dolan, et al.Seattle: University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK1171/.

Pediatrics. 2001. Erratum. Pediatrics 107(6): 1450.Reverby, S. 2009. Examining Tuskegee: The infamous syphilis study

and its legacy. Chapell Hill: University of North Carolina Press.Riepe, F.G., N. Krone, M. Viemann, C.J. Partsch, and W.G.

Sippell. 2002. Management of congenital adrenal hyper-plasia: Results of the ESPE questionnaire. Hormone Re-search 58(4): 196–205.

Ritzen, E.M. 2001. Prenatal dexamethasone treatment of fetusesat risk for congenital adrenal hyperplasia: Benefits andconcerns. Seminars in Neonatology 6(4): 357–362.

Rosner, G., S.B. Shachar, Y. Yaron, andM.I. Evans. 2006. Prenataltherapy of endocrine and metabolic disorders. In Textbook ofperinatal medicine: Volume 1, 2nd edition, ed. A. Kurjak andF.A. Chervenak, 803–812. Abingdon: Informa UK Ltd.

Seckl, J.R., andW.L. Miller. 1997. How safe is long-term prenatalglucocorticoid treatment? JAMA 277(13): 1077–1079.

Silverstein, J.H. 2004. RegardingGCOProject #04-0469 0001 01 PE.Letter to the National Institutes of Health (NIH), September 2.

Silverstein, J.H., R. Rhodes, et al. 2010. Report of ad hoccommittee on Mount Sinai activities of Dr. Maria New tothe Office of Human Research Protections, August 2.

Bioethical Inquiry

Skloot, R. 2010. The immortal life of Henrietta Lacks. NewYork: Crown Publishers.

Sobel, S. 1996. Regarding your proposal to utilize dexametha-sone to treat pregnant women with a [sic] congenital adre-nal hyperplasia, and the requirement of an IND for thisstudy. Letter to M.I. New, Cornell Medical Center.

Speiser, P.W., R. Azziz, L.S. Baskin, et al. 2010a. Congenitaladrenal hyperplasia due to steroid 21-hydroxylase deficien-cy: An Endocrine Society clinical practice guideline. Jour-nal of Clinical Endocrinology and Metabolism 95(9):4133–4160.

Speiser, P.W., R. Azziz, L.S. Baskin, et al. 2010b. A Summaryof the Endocrine Society Clinical Practice Guidelines onCongenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency. International Journal of Pediat-ric Endocrinology 2010(May): 494173. doi:10.1155/2010/494173.

Tamar-Mattis, A. 2010. An attempt to shut down discourseabout a controversial practice will not benefit patients,human subjects, the bioethics community, or the re-search community. The American Journal of Bioethics10(9): 64–66.

Vos, A.A., and H.W. Bruinse. 2010. Congenital adrenalhyperplasia: Do the benefits of prenatal treatment de-feat the risks? Obstetrical and Gynecological Survey65(3): 196–205.

Witchel, S.F., and W.L. Miller. 2012. Prenatal treatment ofcongenital adrenal hyperplasia—not standard of care. Jour-nal of Genetic Counseling, May 26. Epub ahead of print.doi:10.1007s10897-012-9508-8.

Wysocki, B. 2005. As universities get billions in grants, somesee abuses: Cornell doctor blows whistle over use of fed-eral funds, alleging phantom studies. The Wall Street Jour-nal, August 16: A1.

Bioethical Inquiry