Galileo's Middle Finger

by Alice Dreger

  “found safe for mother and child”: See “Prenatal Diagnosis and Treatment,” Maria New Children’s Hormone Foundation.

  studies of efficacy and long-term safety: For a review of how little was actually known about the safety and efficacy of prenatal dexamethasone for CAH in 2010, see Mercè M. Fernández-Balsells et al. “Prenatal Dexamethasone Use for the Prevention of Virilization in Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia Because of 21-Hydroxylase (CYP21A2) Deficiency: A Systematic Review and Meta-Analyses,” Clinical Endocrinology 73, no. 4 (2010): 436–44. This article was published after the OHRP and FDA investigations (discussed in the next chapter) were completed, but the absence of data that it demonstrates was readily apparent to anyone who conducted a basic medical literature search.

  changing brain development: See, for example, Hideo Uno et al. “Neurotoxicity of Glucocorticoids in the Primate Brain,” Hormones and Behavior 28, no. 4 (Dec. 1994): 336–48. See also the concerns raised in Svetlana Lajic, Anna Nordenström, and Tatya Hirvikoski, “Long-Term Outcome of Prenatal Treatment of Congenital Adrenal Hyperplasia,” in Christa E. Flück and Walter L. Miller, eds., Disorders of the Human Adrenal Cortex (Basel: Karger, 2008), 82–98. For a discussion of concerns from animal studies about prenatal dexamethasone increasing cardiovascular disease risk, see Svetlana Lajic, Anna Nordenström, and Tatya Hirvikoski, “Long-Term Outcome of Prenatal Dexamethasone Treatment of 21-Hydroxylase Deficiency,” Endocrine Development 20 (2011): 96–105.

  “the only clinic in the United States”: See “Prenatal Diagnosis and Treatment,” Maria New Children’s Hormone Foundation; and Kitzinger, “Prenatal Diagnosis & Treatment for Classical CAH.”

  funding to study, retrospectively: Evidence of the outcomes study was readily available: “Determining the Long-Term Effects of Prenatal Dexamethasone Treatment in Children With 21-Hydroxylase Deficiency and Their Mothers,” ClinicalTrials.gov, http://clinicaltrials.gov/ct2/show/NCT00617292.

  “have not been determined”: Ibid. (Emphasis added)

  large “accumulated” clinical population: See p. 2 of M. I. New, “Androgen metabolism in childhood,” grant application R01 HD00072-33A1 (approved), National Institutes of Health (New York: Cornell University Medical College, 1996) where New refers to the “large population of prenatally-treated infants” she had “accumulated” for study.

  trying to put a stop: See Dreger, Feder, and Tamar-Mattis, “Prenatal Dexamethasone.”

  a complete absence of any properly controlled scientific studies: This was to be confirmed in the systematic review and meta-analysis published later that year by Fernández-Balsells et al., “Prenatal Dexamethasone.” There has been no placebo-controlled trial of prenatal dexamethasone for CAH and no trials with outcomes judged by independent observers. While the Swedish team has performed a prospective study, New’s U.S. group has tracked outcomes past birth only retrospectively, typically using low-level techniques like phone surveys and questionnaires rather than physical examinations. For an example of the phone survey approach, see Maria I. New et al. “Extensive Personal Experience: Prenatal Diagnosis for Congenital Adrenal Hyperplasia in 532 Pregnancies,” Journal of Clinical Endocrinology & Metabolism 86, no. 12 (2001): 5651–57. For an example of the use of retrospective questionnaires, see Heino F. Meyer-Bahlburg et al., “Cognitive and Motor Development of Children with and without Congenital Adrenal Hyperplasia after Early-Prenatal Dexamethasone,” Journal of Clinical Endocrinology & Metabolism 89, no. 2 (2004): 610–14.

  see if the intervention works in animals: For example, the FDA Web site assures consumers that, in the long process toward approval for drug indications, “companies, research institutions, and other organizations that take responsibility for developing a drug . . . must show the FDA results of preclinical testing in laboratory animals and what they propose to do for human testing.” See Food and Drug Administration, “The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective,” www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm. In 1964, the Declaration of Helsinki codified as its first Basic Principle that clinical research “should be based on laboratory and animal experiments or other scientifically established facts.” Declaration of Helsinki, 18th World Medical Assembly, Helsinki, 1964.

  The Swedish data: See Tatya Hirvikoski, et al., “Cognitive Functions in Children at Risk for Congenital Adrenal Hyperplasia Treated Prenatally with Dexamethasone,” Journal of Clinical Endocrinology & Metabolism 92 (2007): 542–48. It’s interesting that an early report from New’s group on cognitive outcomes hinted at similar possible adverse effects: see P. D. Trautman et al., “Effects of Early Prenatal Dexamethasone on the Cognitive and Behavioral Development of Young Children: Results of a Pilot Study,” Psychoneuroendocrinology 20, no. 4 (1995): 439–49. See below for a discussion of later outcomes studies by New’s group.

  The Swedish group had found: See Svetlana Lajic et al., “Long-Term Somatic Follow-up of Prenatally Treated Children with Congenital Adrenal Hyperplasia,” Journal of Clinical Endocrinology & Metabolism 83, no. 11 (1998): 3872–80.

  between 1 in 10,000 and 1 in 15,000: Maguelone G. Forest, “Recent Advances in the Diagnosis and Management of Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency,” Human Reproduction Update 10, no. 6 (Nov./Dec. 2004): 469–85. The NIH gives the frequency as “about 1 in 10,000 to 1 in 18,000” at MedLine Plus; see www.nlm.nih.gov/medlineplus/ency/article/000411.htm (accessed July 30, 2014).

  drew patients from around the world: Chapter 9 includes a review of what numbers New reported to NIH.

  most common cause of congenital ambiguous genitalia: National Institutes of Health, “Intersex,” MedLine Plus, www.nlm.nih.gov/medlineplus/ency/article/001669.htm (accessed July 30, 2014). CAH actually comes in a number of different forms, and not all forms lead to masculinization in genetic females. The main type we’re interested in here is the form called 21-hydroxylase deficiency.

  substantial natural variation: See Medline Plus, “Congenital Adrenal Hyperplasia,” at http://www.nlm.nih.gov/medlineplus/ency/article/000411.htm.

  ultimately identify as male: Heino F. L. Meyer-Bahlburg, “What Causes Low Rates of Child-Bearing in Congenital Adrenal Hyperplasia?” Journal of Clinical Endocrinology and Metabolism 84, no. 6 (June 1999): 1844–47; Heino F. L. Meyer-Bahlburg et al., “Gender Development in Women with Congenital Adrenal Hyperplasia as a Function of Disorder Severity,” Archives of Sexual Behavior 35, no. 6 (Dec. 2006): 667–84; and Arianne B. Dessens, Froukje M. E. Slijper, and Stenvert L. S. Drop, “Gender Dysphoria and Gender Change in Chromosomal Females with Congenital Adrenal Hyperplasia,” Archives of Sexual Behavior 34, no. 4 (Aug. 2005): 389–97.

  opted to abort: Selective abortion of females with CAH is reported, for example, in Arlene B. Mercado et al., “Extensive Personal Experience: Prenatal Treatment and Diagnosis of Congenital Adrenal Hyperplasia Owing to Steroid 21-Hydroxylase Deficiency,” Journal of Clinical Endocrinology and Metabolism 80, no. 7 (July 1995): 2014–20.

  A 1984 paper: Michel David and Maguelone G. Forest, “Prenatal Treatment of Congenital Adrenal Hyperplasia Resulting from 21-Hydroxylase Deficiency,” Journal of Pediatrics 105, no. 5 (Nov. 1984): 799–803.

  making the intervention available: See Chapter 9 for a review of the history of New’s use of prenatal dexamethasone.

  Dr. New tells the families: Maria I. New, lecture presented at conference for CARES Foundation, Weill Medical College of Cornell University, New York, Nov. 14, 2001.

  “done well in very few centers”: Ibid.

  giving birth prematurely: Concerned researchers have been tracking possible unintended consequences of the use of prenatal steroids for premature birth risk; see, for example, National Institutes of Health Consensus Development Panel, “Antenatal Corticosteroids Revisited: Repeat Courses,” Statement of NIH Consensus Development Conference, Aug. 17–18, 2000, Obstetrics and Gynecology 98, no. 1 (2001): 144–
50; see also Noel P. French et al. “Repeated Antenatal Corticosteroids: Effects on Cerebral Palsy and Childhood Behavior,” American Journal of Obstetrics and Gynecology 190, no. 3 (Mar. 2004): 588–95.

  families steadily learned: For an example of a woman knowing to call Maria New, “a total stranger,” as soon as she was pregnant with a fetus who might have CAH, see Catherine Elton, “A Prenatal Treatment Raises Questions of Medical Ethics,” Time, June 18, 2010, http://content.time.com/time/health/article/0,8599,1996453,00.html.

  pregnancy category C: FDA Pregnancy Categories, http://depts.washington.edu/druginfo/Formulary/Pregnancy.pdf (accessed July 30, 2014).

  “despite potential risks”: Ibid.

  the DES disaster: For a history of DES, see Nancy Langston, Toxic Bodies: Hormone Disruptors and the Legacy of DES (New Haven, CT: Yale University Press, 2010).

  study published in 1953: William J. Dieckmann et al., “Does the Administration of Diethylstilbestrol During Pregnancy Have Therapeutic Value?,” American Journal of Obstetrics and Gynecology 66, no. 5 (Nov. 1953): 1062–82.

  serious question in 1971: See Langston, Toxic Bodies; see also Centers for Disease Control, “About DES,” www.cdc.gov/DES/CONSUMERS/about (accessed July 30, 2014).

  fatal vaginal cancer: The first report of this cancer cluster’s tie to DES was Arthur L. Herbst, Howard Ulfelder, and David C. Poskanzer, “Adenocarcinoma of the Vagina: Association of Maternal Stilbestrol Therapy with Tumor Appearance in Young Women,” New England Journal of Medicine 284, no. 15 (Apr. 15, 1971): 878–81.

  Penny Stone: See DES Action, “Meet the Woman Who Was the First to Connect DES and Cancer,” DES Action Voice, no. 134 (Fall 2012): 8.

  reproductive cancers: For a good overview of the harms caused by prenatal DES, see National Cancer Institute, “Diethylstilbestrol (DES) and Cancer,” www.cancer.gov/cancertopics/factsheet/Risk/DES (accessed July 30, 2014).

  Frances Oldham Kelsey: See Gardiner Harris, “The Public’s Quiet Savior from Harmful Medicines,” The New York Times, Sept. 13, 2010, http://www.nytimes.com/2010/09/14/health/14kelsey.html.

  ten thousand children in Europe: Centers for Disease Control and Prevention, “Thalidomide,” http://www.cdc.gov/healthcommunication/toolstemplates/entertainmented/tips/thalidomide.html.

  David Sandberg: David Sandberg reviewed this account of our discussions and confirmed its accuracy, personal communication, Oct. 13, 2012.

  sixty to a hundred times: Walter L. Miller, “Prenatal Treatment of Classic CAH with Dexamethasone: Con,” Endocrine News (Apr. 2008): 16–18.

  All we had were reports: The problems with this approach are alluded to in Fernández-Balsells et al., “Prenatal Dexamethasone.”

  data coming out of Sweden: See Hirvikoski et al., “Cognitive Functions.”

  missing or choosing not to participate: In 2010, New’s chief collaborator, Heino Meyer-Bahlburg, admitted that “fewer than 50% of mothers and offspring have responded to questionnaires”: in Phyllis W. Speiser et al., “A Summary of the Endocrine Society Clinical Practice Guidelines on Congenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency,” International Journal of Pediatric Endocrinology, May 2010, www.ijpeonline.com/content/2010/1/494173; for quotation, see “3. Prenatal Treatment of CAH.”

  “fetal programming”: The risk of fetal programming from prenatal dexamethasone was raised as early as 1997; see Jonathan R. Seckl and Walter L. Miller, “How Safe Is Long-Term Prenatal Glucocorticoid Treatment?,” Journal of the American Medical Association 277, no. 13 (Apr. 2, 1997): 1077–79. For others raising the concern, see Hirvikoski et al., “Cognitive Functions.” For more recent analyses of prenatal glucocorticoids and the programming of adult disease, see Anjanette Harris and Jonathan Seckl, “Glucocorticoids, Prenatal Stress, and the Programming of Disease,” Hormones and Behavior 59, no. 3 (Mar. 2011): 279–89.

  Wall Street Journal: Bernard Wysocki Jr., “As Universities Get Billions in Grants, Some See Abuses: Cornell Doctor Blows Whistle over Use of Federal Funds, Alleging Phantom Studies,” Wall Street Journal (Aug. 16, 2005): A1.

  Sarafoglou went to the Feds: Ibid.

  only about 80 percent of the time: The authors of the formal pediatric endocrine consensus that emerged in 2010 (discussed in the next chapter) noted the poor quality of efficacy data and concluded only that “the groups advocating and performing prenatal treatment appear to agree that it is effective in reducing and often eliminating virilization of female fetal genitalia and that the success rate is about 80–85%”; see Phyllis W. Speiser et al., “Congenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline,” Journal of Clinical Endocrinology and Metabolism 95, no. 9 (Sept. 2010): 4133–60.

  had been warning: Seckl and Miller, “How Safe.”

  Miller had finally declared: Miller, “Prenatal Treatment,” 17.

  numerous medical societies: See, for example, Joint LWPES/ESPE CAH Working Group, “Consensus Statement on 21-Hydroxylase Deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pædiatric Endocrinology,” Journal of Clinical Endocrinology and Metabolism 87, no. 9 (Sept. 2002): 4048–53.

  American Academy of Pediatrics: Jaime Frias, Lenore S. Levine, Sharon E. Oberfield, et al., “In Reply,” (letter to the editor) Pediatrics, vol. 107, no. 4 (2001): 805. The letter referred to “the memory of the tragedies associated with prenatal use of dexamethasone and thalidomide,” a line the authors later corrected to read “use of DES (diethylstilbestrol) and thalidomide”; see erratum, Pediatrics 107, no. 6 (June 2001): 1450, http://pediatrics.aappublications.org/content/107/6/1450.full.

  I wrote to her: Alice Dreger to Maria New, e-mail communication, Dec. 8, 2009.

  Miami: Maria I. New, “Long Range Outcome of Prenatal Treatment,” conference presentation at 2nd World Conference, Hormonal and Genetic Basis of Sexual Differentiation Disorders and Hot Topics in Endocrinology, Jan. 15, 2010, Miami Beach.

  was very poor: This was confirmed in Meyer-Bahlburg’s report in Speiser et al., “A Summary of the Endocrine Society Clinical Practice Guidelines.”

  at least one boy exposed: The Swedish team formally published the evidence suggesting that boys exposed prenatally might be hypomasculinized in 2011 and 2012. See Lajic, Nordenström, and Hirvikoski, “Long-Term Outcome”; see also Tatya Hirvikoski et al., “Prenatal Dexamethasone Treatment of Children at Risk for Congenital Adrenal Hyperplasia: The Swedish Experience and Standpoint,” Journal of Clinical Endocrinology and Metabolism 97, no. 6 (June 2012): 1881–83, doi:10.1210/jc.2012-1222.

  plugging prenatal dex: See, for example, Maria I. New and Nathalie Josso, “Disorders of Sexual Differentiation,” in Lee Goldman and J. Claude Bennett, eds., Cecil Textbook of Medicine, 21st ed. (Philadelphia: W. B. Saunders, 2000): 1297–1306; Maria I. New, Lucia Ghizzoni, and Karen Lin-Su, “An Update of Congenital Adrenal Hyperplasia,” in Fima Lifshitz, ed., Pediatric Endocrinology, 5th ed. (New York: Informa Healthcare, 2007): 227–45.

  Marsha Rappley: Conversation with Marsha Rappley; account confirmed by e-mail, Oct. 26, 2012.

  another e-mail message: Alice Dreger to Maria New, e-mail communication, Jan. 24, 2010.

  from Jeffrey Silverstein: Jeffrey H. Silverstein to Alice Dreger, e-mail communication, Jan. 26, 2010.

  I asked Dr. Silverstein to clarify: Alice Dreger to Jeffrey H. Silverstein, e-mail communication, Jan. 26, 2010.

  CHAPTER 8: DOCTOR, MY EYES

  American medical ethics regulations: See the Code of Federal Regulations, Title 45, Part 46; for a sociological and historical analysis of institutional review boards (local ethics committees) in the United States, see Laura Stark, Behind Closed Doors: IRBs and the Making of Ethical Research (Chicago: University of Chicago Press, 2011).

  New consistently described: For examples, see “Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia,”
Maria New Children’s Hormone Foundation, www.newchf.org/testing.php (accessed July 30, 2014). See also Elizabeth Kitzinger, “Prenatal Diagnosis & Treatment for Classical CAH,” CARES Foundation Newsletter 2, no. 1 (Winter 2003): 15, www.caresfoundation.org/productcart/pc/news_letter/winter02-03_page_9.htm. See also Maria I. New, lecture presented at conference for CARES Foundation, Weill Medical College of Cornell University, New York, Nov. 14, 2001.

  “to establish that prenatal treatment with dexamethasone is safe”: The same year New was describing dex as “safe” at the CARES Foundation meeting (ibid.), she told the NIH in her “Application for Continuation Grant,” “We must now establish that prenatal treatment with dexamethasone is safe and has no long-term consequences”; Maria I. New, application for continuation grant, “Androgen Metabolism in Childhood,” grant 5-R37-HD00072-37 (approved), National Institute of Child Health and Human Development (New York: Weill Cornell Medical College, 2001), quotation on p. 46. She specifically listed “prenatal treatment” as part of her “research plan” (p. 43). In the same grant application, New also told NIH: “This study is conducted . . . by FDA permission” (p. 47); I show below that there is no evidence she had such permission. As noted below, as late as 2006 she was still specifically naming dex-exposed fetuses as subjects of research for NIH grant purposes.

  “human subjects of research”: In her 2001 “Application for Continuation Grant” (ibid.), New described the sources of her human subjects this way: “Sources of human subjects are referrals from local and distant physicians who care for pregnant women at risk for having a fetus with CAH” (p. 47). Naming “the strengths of our group,” New told the NIH, “We are the only group in the United States carrying out prenatal diagnosis and treatment of CAH and have thus accumulated a large population of prenatally treated patients to study” (p. 34).