Experimental status of prenatal dexamethasone for CAH re-affirmed
For several decades now, prenatal dexamethasone has been used off-label by some physicians treating pregnant women at risk for carrying a female fetus with 21-hydroxylase deficiency, the most common form of congenital adrenal hyperplasia.
The primary goal of this treatment is preventing development of ambiguous genitalia in the fetus. Administration of dexamethasone for this purpose has long been controversial, both in the endocrine and the bioethics communities. Concerns have included the wisdom of using a class C steroid known and intended to alter fetal development for treatment of a non-life-threatening condition, and the ethics of using such a treatment when at least seven of eight fetuses treated will bear the risks, yet derive no benefit by virtue of not being 46,XX congenital adrenal hyperplasia (CAH)-affected.
Nonetheless, it appears that prenatal dexamethasone for CAH eventually came to be viewed by many as standard of care. In fact, expert groups visiting this issue have repeatedly come to the conclusion that very little is known about the long-term safety of prenatal dexamethasone for CAH and that therefore particularly given how early prenatal dexamethasone is started (as soon as pregnancy is confirmed) extreme caution is warranted.
A recently issued consensus statement underscores that practitioners should regard this treatment as experimental. The 2010 Endocrine Society Clinical Practice Guideline regarding the administration of prenatal dexamethasone for CAH was co-sponsored by the American Academy of Pediatrics, the Pediatric Endocrine Society, the Society for Pediatric Urology, the European Society for Pediatric Endocrinology, the European Society of Endocrinology, the CARES Foundation, and the Androgen Excess and Polycystic Ovary Syndrome (PCOS) Society.
The latest expert consensus states: We recommend that prenatal therapy continue to be regarded as experimental. Thus, we do not recommend specific treatment protocols. We suggest that prenatal therapy be pursued through protocols approved by Institutional Review Boards at centers capable of collecting outcomes data on a sufficiently large number of patients so that risks and benefits of this treatment can be defined more precisely.
The GeneReviews entry on CAH caused by 21-hydroxylase deficiency, written by Drs. Saroj Nimkarn and Maria New, now reaches a similar conclusion: Prenatal treatment should continue to be considered experimental and should only be used within the context of a formal IRB-approved clinical trial. As with the Endocrine Society consensus, the GeneReviews article no longer provides guidelines on how to employ the treatment.
In reaching a similar conclusion on the experimental and concerning nature of prenatal dexamethasone for CAH, a committee of the American Academy of Pediatrics that convened in 2001 wrote in the journal Pediatrics: The maxim of first do no harm requires a cautious, long-term approach, which is why the Academy Committee unanimously agrees that prenatal glucocorticoid therapy for CAH should be confined to centers doing controlled prospective, long-term studies. The memory of the tragedies associated with prenatal use of DES and thalidomide demands no less.
Unfortunately, long-term study of those treated has been spotty and problematic. A report on the 2010 consensus states that that task force was hampered by the lack of high-quality data. Of 1,083 studies originally identified, only four met the quality criteria agreed upon by the sponsoring groups. Outcome data on prenatal treatment are suspect. Most are derived from questionnaires, not from physical examination of the offspring. And because dexamethasone prenatal treatment is relatively new, no offspring have yet reached middle age where many problems can be expected to present.
Clinicians in Sweden, a leader in this area, have conducted prospective clinical trials of prenatal dexamethasone for CAH. Their work has raised concerns about unintended cognitive effects on treated offspring. Swedish clinicians are concerned enough about the cognitive outcomes of treated children that they have stopped use of the treatment. They are continuing to monitor those who underwent treatment in utero.
Most (if not all) of those treated in the US appear to have been treated outside of prospective, long-term studies. A 2007 outcome study clinical protocol to the Rare Diseases Clinical Research Network (RDCRN) seeks now to locate those who have been treated, but again primarily employs questionnaires rather than extensive physical and cognitive examinations. Moreover, it is notable (when taken in conjunction with findings and concerns in Sweden) that the RDCRN outcome study specifically excludes all patients with mental impairment which prevents understanding of questionnaires.
Many major hospitals are now reconsidering their protocols for prenatal use of dexamethasone in fetuses possibly affected by CAH. One of the leading centers in developing this treatment, the Mount Sinai School of Medicine, has stated in response to questions from the federal Office for Human Research Protections:
The Committee determined that there are widely differing opinions amongst the staff, which some staff members expressing significant concerns regarding the use of dexamethasone for the prenatal treatment of CAH. A particular concern is the current necessity to treat potentially unaffected fetuses until a diagnosis is determined. Therefore, the Committee concluded that the clinical use of dexamethasone in this situation should require a rigorous informed consent process with detailed documentation that the risks and benefits of this treatment have been clearly communicated to the parents making a decision to engage in prenatal treatment. The Committee also recommends that this issue be referred to the Medical Board of The Mount Sinai Hospital for further consideration of the consent issue.
All pediatric endocrinologists should know of the overwhelming expert consensus that prenatal dexamethasone for CAH should not be used outside of prospective, long-term clinical trials run from centers large enough to collect meaningful data, with IRB oversight and stringent requirements for informed consent. Such caution will help protect the pregnant women and fetuses who may be treated, as well as physicians who may be liable for harm after inadequate informed consent.
Ellen K. Feder, PhD, is associate professor of philosophy at American University. Anne Tamar-Mattis, JD, is executive director of Advocates for Informed Choice, Cotati, Calif. She welcomes responses to this article at firstname.lastname@example.org. Alice Dreger, PhD, is professor of clinical medical humanities and bioethics at Northwestern University Feinberg School of Medicine.
For more information:
- Frias J. Pediatrics. 2001;107:805.
- Lajic S. Endocr Dev. 2011;20:96-105.
- New MI. Long-term outcome in offspring and mothers of dexamethasone-treated pregnancies at risk for classical congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. In: Mount Sinai School of Medicine: Rare Diseases Clinical Research Network; 2007.
- Nimkarn S. 21-hydroxylase-deficient congenital adrenal hyperplasia. GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. University of Washington, Seattle; 1997-2006. Available at: www.genetests.org.
- Speiser PW. J Clin Endocrinol Metab. 2010;95:4133-4160.
Disclosure: Drs. Dreger and Feder and Ms. Tamar-Mattis report no relevant financial disclosures.