Cognitive function is reduced in healthy girls exposed to early prenatal dexamethasone, which suggests the therapy should not be used in fetuses at risk for congenital adrenal hyperplasia before genotype is known, according to researchers.
Svetlana Lajic, MD, PhD, of the department of Women’s and Children’s Health, pediatric endocrinology unit at Karolinska University in Sweden, and colleagues evaluated children and adolescents aged 7 to 17 years whose mothers were treated with dexamethasone while pregnant (n = 34; 16 girls) and untreated controls (n = 66; 36 girls) from Sweden to determine the long-term cognitive effects of prenatal dexamethasone therapy. Participants completed standardized neuropsychological tests and questionnaires.
Using the Wechsler Intelligence Scales for Children-III, researchers found significant interactions between dexamethasone and sex for nonverbal processing speed (P = .044), nonverbal intelligence (P = .013) and verbal intelligence (P = .025). The interaction between dexamethasone and sex for verbal working memory nearly reached significance (P = .074). Researchers observed a negative main effect of dexamethasone on verbal working memory (P = .005). Girls with early prenatal dexamethasone exposure scored lower than female controls on all tests (nonverbal processing speed, P = .068; nonverbal intelligence, P = .021; verbal intelligence, P = .014; and verbal working memory, P = .001).
No significant differences were found between boys with early prenatal dexamethasone and male controls.
“Our results suggest that early prenatal [dexamethasone] exposure, as employed in prenatal treatment of fetuses at risk for [congenital adrenal hyperplasia], is likely to affect cognitive functions in health girls, ie, children who do not benefit from the treatment,” the researchers wrote. “It can therefore not be considered safe to use this therapy in the context of [congenital adrenal hyperplasia] although extended studies in additional cohorts around the world are warranted. If [dexamethasone] is still offered, it is essential that information about the risks and benefits of the treatment is given to the pregnant couple. The treatment should be questioned and should only be offered within the framework of a clinical study with longitudinal long-term follow-ups of mothers and children. Given the importance of working memory for academic performance, screening for deficits should be performed and interventional strategies might be needed in [dexamethasone]-treated cases.” – by Amber Cox
Disclosure: The researchers report no relevant financial disclosures.
Ellen K. Feder
Researchers at the Karolinska Institute in Sweden have published another paper showing negative cognitive effects for children treated prenatally with dexamethasone in pregnancies at risk for involving a fetus with congenital adrenal hyperplasia. The paper contains a strongly worded conclusion, mirroring growing concerns about the intervention: “It can therefore not be considered safe to use.”
The Swedish study is small and might well be called into doubt or even refuted with additional study, but it is worth remembering why we don’t have more and better data: the vast majority of prenatal dexamethasone interventions for CAH risk have been done outside of prospective long-term studies. This in spite of the fact that every pediatric consensus report ever issued on this intervention has said it should be strictly limited to prospective, institutional review board-approved, long-term trials (Frias J, et al. Pediatrics. 2001;107(4):805; Joint LWEPES/ESPE CAH Working Group. J Clin Endocrinol Metab. 2002;87(9):4048-4053; Speiser PW, et al. J Clin Endocrinol Metab. 2010;95(9):4133-4160).
To date, almost 90% of the children exposed to this intervention have stood no chance to benefit. This intervention does not treat or prevent life-threatening conditions. Yet to this day, there is not even a single observer-blinded efficacy trial for prenatal dexamethasone, no less a placebo-controlled trial.
And safety? We have virtually no meaningful scientific data there other than what little has come from Sweden. In the wake of thalidomide and diethylstilbestrol, clinicians have for 30 years employed a prenatal drug intended to significantly change the course of fetal development with no animal modeling of this use, no meaningful efficacy studies, and only one long-term controlled prospective trial running long enough to produce any useful data (Hirvikoski T, et al. J Clin Endocrinol Metab. 2012;doi:10.1210/jc.2012-1222).
In the United States, thousands of pregnant women have been offered and apparently also given this treatment, outside of trials, under claims that it had been found safe and effective. These claims of safety and efficacy were repeatedly made by the leading proponent of the intervention who simultaneously sought and was granted NIH funding to ascertain safety and effectiveness by studying the same families retrospectively (Dreger A, et al. J Bioeth Inq. 2012;9(3):277-294; Dreger A. Galileo’s Middle Finger: Heretics, Activists and the Search for Justice in Science. 2015, Penquin Press).
The scandalous history of prenatal dexamethasone for CAH remains a present reality. Even if the Swedish group were not finding significant harm — something that should hardly surprise us given that this is a drug specifically selected because it crosses the placental barrier and changes fetal development — what has happened here is understood by any reasonably independent observer as an affront to medical science, to medical ethics and especially to families affected by CAH.
Disclosure: Dreger reports receiving speaking and writing fees for the history and ethics of prenatal dexamethasone for intersex prevention. Feder reports no relevant financial disclosures.
The current study looks at long-term effects of prenatal dexamethasone treatment on pregnancies at risk for congenital adrenal hyperplasia. This treatment has long been controversial, and the Swedish group that authored the study stopped offering prenatal dexamethasone in 2010 when severe adverse events emerged (Hirvikoski T, et al. J Clin Endocrinol Metab. 2007;92:542-548). The authors are to be commended, both for their cautious approach, and for publishing long-term results which show “alarming” effects on working memory in addition to other negative cognitive outcomes.
These effects were clear enough that the authors conclude: “It can therefore not be considered safe to use this therapy in the context of [congenital adrenal hyperplasia].” This is compelling commentary for anyone who may have continued routinely recommending such treatment even after the 2010 issuance of Endocrine Society Task Force guideline stating the experimental therapy should only be offered in the context of clinical trials (Speiser PW, et al. J Clin Endocrinol Metab. 2010;95(9):4133-4160).
Disclosure: Tamar-Mattis reports no relevant financial disclosures.