welcome to fetaldex.org

 

NEW SUMMARY OF FINDINGS:

A new paper in the Journal of Bioethical Inquiry traces the history of what happened with prenatal dexamethasone for CAH. We wrote it to be accessible to most readers, so if you want a good overview, download and read the article for free by clicking here. You can also read the “Dex Diaries” series here.


UPDATE ON RISK WARNINGS FROM RESEARCHERS:

Six new medical journal articles are further raising concerns about the use of prenatal dexamethasone for the attempted prevention of sex atypicality in congenital adrenal hyperplasia. We summarize those five here. (Below the cut-line, you can read a more general explanation of what we’re talking about if you’re not sure what the issue here is.)


1. PEDIATRIC ENDOCRINOLOGISTS WARN OBSTETRICIANS IN TOP OB JOURNAL NOT TO USE PRENATAL DEX FOR CAH, SAYING RISKS OUTWEIGH BENEFITS:

In a new article in the top obstetrical journal, The American Journal of Obstetrics & Gynecology, two pediatric endocrinologists have reviewed the evidence available for prenatal dexamethasone for CAH and conclude: “the benefits do not warrant the risks, and hence [...] first-trimester dexamethasone should not be used to ameliorate genital virilization in CAH.” The authors are Walter L. Miller, MD, distinguished professor of endocrinology at UCSF School of Medicine, and Selma Feldman Witchel, MD, Division of Pediatric Endocrinology, Children’s Hospital of Pittsburgh.


2. SWEDISH DEX RESEARCH TEAM REPORTS 1 IN 5 CHILDREN EXPOSED SUFFERS “SEVERE ADVERSE EVENT”, SHUTS DOWN INTERVENTION:

The Swedish study group -- the only group to ever study this intervention in a prospective, continuous, controlled manner -- now reports that approximately 1 in 5 children exposed prenatally have suffered a serious adverse event. In a journal article detailing outcomes on 43 children treated in Sweden and Norway during 1985-1995, when compared to controls,

[i]n general, treated children were born at term and were not small for gestational age. As a group, they did not exhibit teratogenous effects/gross malformations, although eight severe adverse events were noted in the treated group, compared with one in the control group. Three children failed to thrive during the first year of life; in addition, one had developmental delay and hypospadias; one had hydrocephalus; two girls were born small for gestational age, and one of these girls was later diagnosed with mental retardation; and one child had severe mood fluctuations that caused hospital admission. In the control group, only one child was admitted because of Down’s syndrome.

How is it the Americans haven’t found a serious adverse event rate of approximately 1 in 5? Probably because they haven’t looked. American physicians, under the strong guidance of Maria New, have done this intervention outside prospective controlled long-term studies, in spite of all the calls from all the medical groups over the years NOT to do it outside these kinds of studies because this is NOT standard of care. If you don’t watch children prenatally treated continuously, you’re not going to pick up this kind of data.

As for the cognitive and behavioral outcomes, the Swedish team admits, “the small sample size, relatively high refusal rate, and the retrospective study design limited the conclusiveness of the results” of their follow-up of the behavioral development in 40 Swedish children treated prenatally. Nevertheless, they did find that:

[a]n adverse effect was observed in the form of impaired verbal working memory in CAH-unaffected short-term-treated cases [i.e., the children who were not the intended targets of the intervention]. The verbal working memory capacity correlated with the children’s self-perception of difficulties in scholastic ability, another measure showing significantly lower results in CAH-unaffected, DEX-exposed children. These children also reported increased social anxiety. In the studies on gender role behavior, we found indications of more neutral behaviors in DEX-exposed boys.

This unintended effect -- relative “feminization” of the boys “accidentally” exposed to dex prenatally -- again suggests unintended brain effects of the intervention. (And see this page for the apparent intentions of the leading American research team with regard to gender and sexual orientation. You have to figure that a team interested in preventing lesbians probably wasn’t meaning to accidentally create gay boys in the process. . . )


3. NEW PRIMATE STUDY (AGAIN) SUGGESTING BRAIN DAMAGE RISK:

See the paper’s abstract here. Note this is one of many animal models showing risk to the developing primate brain from prenatal glucocorticoids. Animals studies also suggest high risk of “programming effects” like those seen with DES.


4. NEW STUDY IN PEDIATRICS SUGGESTS POTENTIAL INCREASED RISK OF HEART DISEASE AND DIABETES:

“Antenatal glucocorticoid exposure in preterm infants is associated with increased aortic arch stiffness and altered glucose metabolism in early adulthood,” i.e., increased risk of heart disease and diabetes. Prenatal dexamethasone for CAH is an antenatal glucocorticoid, started much earlier in pregnancy than for prematurity. Abstract here.


5. JOURNAL OF GENETIC COUNSELING PUBLISHES ARTICLE DEMONSTRATING PRENATAL DEX FOR CAH IS NOT STANDARD OF CARE:

See the new article here. (So why are pregnant women at risk for having a child with CAH still being told “this is what you do”? Because the clinicians pushing it are either ignorant of the facts or . . . ?)


6. MEYER-BAHLBURG AND NEW’S GROUP RELEASE PAPER CONFIRMING THAT OUR CONCERNS ARE ACCURATE:

This study in the European Journal of Endocrinology includes some cognitive outcome data for only 67 children exposed to dexamethasone for the purpose of prevention of development of sex atypicality in girls with CAH, including 8 children who turned out to be the target population type (girls with CAH). So among this study group, 59 of the children were prenatally exposed in the first trimester to risks associated with a glucocorticoid dose 60-100 times normal physiological levels, with no chance of benefit, something animal studies have suggested could lead to brain damage and fetal programming (like DES). This is a major reason why clinicians have been so worried about cognitive and metabolic outcomes of this intervention -- because 7/8 of those exposed prenatally stand no chance to benefit.

This new paper helpfully confirms what we've been saying: the use of prenatal dexamethasone for CAH by New's group has been ethically and scientifically deeply problematic -- ethically problematic in part because the methods used have been so very unscientific. (If you don't study an intervention like this carefully, like the Swedes have tried to do, it can take a long, long time before you find out what it actually does, which means many children may be unnecessarily put in danger in the interim.)

The new publication's study population amounts to a tiny fraction of those exposed via New's consultations. How many did she help to expose? Well, in 2003, New claimed to have "treated" over 600 fetuses with prenatal dex for CAH; New's 2006 grant progress report indicated "that we have now diagnosed and/or treated 768 fetuses" with prenatal dex for CAH; confusingly, New's 2001 NIH "application for continuation grant" provides a table describing numbers of human subjects under the "specific [study] aim" called "prenatal dx and treatment in families and risk," and there the number of subjects is stated as 2,144. (She repeatedly used her large population as a reason the NIH should fund her and Meyer-Bahlburg’s follow-up studies.)

So depending on which of New's claims as to number prenatally exposed is accurate, New should have accumulated somewhere between 600 and 2,144 children exposed, yet here they tell us what happened to only 67. Her group should also include between 98 and 268 CAH girls who were long-term dex exposed. But this study only tells us about 8 girls long-term dex exposed via New's consultation.

Thus it would appear that the new study represents somewhere between 3% and 12% of New's prenatally exposed population.

There is little chance this population is a representative sample, or that this study can tell us anything meaningful about dose effect. Those children who were studied in this new report were "selected" via convenience sampling performed retrospectively. Moreover, although the publication purports to seek information on the effects of dex exposure, the degree of dex exposure varies wildly among the 8 girls long-term treated. They range in exposure from 9 weeks of fetal life to 39 (!) weeks of fetal life. This means that among the 8, exposure duration differed by as much as four times, a huge variation, and a huge variation among a small convenience sample studied retrospectively.

The new study focuses on cognitive outcomes and conclude: "Our studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory,” i.e., the Swedish team’s findings, “while our findings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about potentially adverse cognitive aftereffects of such exposure.”

In fact, the data gathered in this small, problematic sample from Meyer-Bahlburg and New’s group show there are some "positive" cognitive outcomes in the short-term treated children. which the authors note is weird. It suggests that either short-term prenatal dex exposure is good for kids, or this is in fact not a representative sample. In their discussion, the authors try to explain the lack of corroboration by other studies (or by logic) for these outcomes, but they don't provide the most obvious explanation: This is not, in fact, any kind of representative sample of those exposed.

The Swedes, in stark comparison to New's group, have studied this off-label intervention prospectively in a control trial, with full ethics board approval from start to finish. Their findings have disturbed them enough to shut down the intervention portion of their study for concerns about adverse effects. You can no longer get prenatal dex for CAH in Sweden, because it is considered too dangerous, even within clinical trials. In a newly-published report, 1 in 5 children dex-exposed had a severe adverse event in the Swedish prospective control trial. (See the top of this page for excerpts from that report.)

 New's group has not studied dex in a way that would produce this kind of data. In the US, at-risk pregnancies are still treated outside of clinical trials, with no prospective long-term studies, with New still describing the intervention as "safe for mother and child." So who do you suppose the Swedes are primarily yelling at when they conclude, "We find it unacceptable that, globally, fetuses at risk for CAH are still treated prentally with DEX without follow-up"? 

So really, what the new paper from Meyer-Bahlburg and New actually replicates is our findings, that this has been an ethical and scientific disaster.

We note that the CoI disclosure on the New and Meyer-Bahlburg new publication says this: "None of the authors have a conflict of interest that could be perceived as prejudicing the impartiality of the research record." Regardless of this "disclosure," it seems it is more than time for this population to be studied in as meaningful way as possible by a group that has not staked their reputations on not having harmed hundreds of children drawn into this high-risk intervention under the claim that it has been shown "safe for mother and child."

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Purpose of this website: This website seeks to raise ethical concerns about the prenatal use of dexamethasone (a Class C steroid) when it is given to pregnant women to attempt to prevent female fetuses from developing genitals that are atypical, and when it is given by clinicians to also prevent females from being psychologically “masculnized,” i.e., tomboyish, more aggressive than average girls, and ultimately lesbian of bisexual in sexual orientation.

An excellent plain-language introduction to this topic is provided via this article at Time magazine.

Our primary concern is that women given this drug may have been experimented upon without their knowledge and without human research protections. It appears that some researchers, notably Dr. Maria New’s team, may have treated and still be treating pregnant women with prenatal dex, off-label and outside any clinical trials or human subjects research protections, even while they are concerned enough to be studying the mothers and children after the birth. In other words, it appears these clinician-researchers consider the off-label use of this drug questionable enough to get grants to study its long-term safety, yet not questionable enough to manage as formal clinical trials during pregnancy when they are actively putting the mothers and their children at risk.

This is not our only concern. You can read about our concerns one-by-one by going to our “issues page.

What the medical community as a whole says: Contrary to Dr. New’s advertising of this treatment as “safe for mother and child,” the medical community has repeatedly come to the consensus that this use of prenatal dex remains risky enough that it should only be attempted within IRB-approved clinical trials. That consensus has recently been reiterated, indeed even more strongly. Yet, as we have documented, it appears hundreds if not many thousands of women have been subjected to this experimental use without giving informed consent to experimentation. This may still be going on today, although it appears that, since we started our efforts, most clinicians now know about the experimental nature of this treatment.

The worries about prenatal dex for CAH: According to a recent article in Endo Daily reporting on the Task Force that produced the latest consensus to label prenatal dex experimental, dexamethasone “crosses the placental barrier and may affect the fetal hypothalamic-pituitary-adrenal axis. Prenatal use of the drug is associated [with] low birth weight, central nervous system effects, cleft palate, liver enlargement, a decrease in fetal beta cells and other negative outcomes in animals. The human literature suggests that prenatal dexamethasone carries a 1.7 odds ratio for orofacial clefts and decreases birth weight by about 0.5 kg.”

The Endo Daily article continues: “The task force [reviewing the evidence about the risks and benefits of prenatal dex for CAH] was hampered by the lack of high-quality data. Of 1,083 studies originally identified [by the task force], only four met the quality criteria agreed upon by the sponsoring groups. [...] Side effects included stillbirth (odds ratio 1.27), malformation (odds ratio 1.51), maternal edema (odds ratio 1.83) and maternal striae (odds ratio 1.62). 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.”

Which fetuses are targeted: Prenatal dexamethasone is recommended by some physicians to pregnant women who are believed to be “at risk” for having a female fetus with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia (CAH). In CAH, the adrenal glands produce abnormally high levels of androgens, which are sometimes called “masculinizing” hormones. This form of CAH can result in a girl being born with genitals that look in-between the male and female types (e.g., she may have a large clitoris) and with a confluence of her urethra and vagina (a urogenital sinus). Studies have also indicated that these girls’ brains are “masculinized” in the womb, meaning that, on average, they are also more likely than other girls to be tomboyish and to grow up to be lesbian in sexual orientation.

The goals of the prenatal dexamethasone treatment: Importantly, CAH is a serious endocrine disease (a hormone imbalance) which prenatal dexamethasone does absolutely nothing to cure. A child with CAH who was treated with prenatal dexamethasone is still born with CAH and must have lifelong endocrine management to be safe. So why is prenatal dexamethasone used? Most clinicians who administer it are seeking to prevent ambiguous genitalia. Read more about that here. Some clinicians appear to also administer it in the hopes of preventing lesbianism and gender nonconformity. Read about that here.

Actions have we taken to follow up on our concerns: You can read the various letters of concern and formal complaints at our correspondence page. That page also shows responses to letters of concern and complaints. You can read findings of our FOIA requests at our FOIA page. (We are still awaiting results of 4 additional FOIA requests.) At the page on disseminating the truth about standards of care, you can read about what we’ve done to try to make sure health care professionals know the status of prenatal dex for CAH.

If you want to learn more, go to the FAQ page or the issues page.