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
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
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
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
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
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
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
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:
- Speiser PW. J Clin Endocrinol Metab.
Disclosure: Drs. Dreger and Feder and Ms. Tamar-Mattis report no
relevant financial disclosures.