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Is Prenatal Dexamethasone Safe: The Baby Makers’ Hubris

Published on January 20, 2022

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For some reason, maybe hubris, medical science seems doomed to repeat the sins of their fathers. The lessons of thalidomide and diethylstilbestrol (DES) of generations past (present and future because of transgenerational effects) have not been learned. Reproductive endocrinologist, obstetricians and others tasked with protecting maternal and fetal health are at it again; happily and blindly dosing pregnant women with synthetic steroids with neither the evidence to support their efficacy nor the research to prove safety.

Prenatal Dexamethasone and Congenital Adrenal Hyperplasia

Dexamethasone or DEX is a synthetic corticosteroid that mimics the anti-inflammatory and immunosuppressant effects of endogenous cortisol. DEX is used in the treatment of variety of conditions from arthritis to cancer. Since DEX easily crosses the placental barrier and can have detrimental effects to the developing fetus, it is considered unsafe for pregnant women. Per the FDA:

Dexamethasone is listed as a pregnancy Category C drug. Corticosteroids have been shown to be teratogenic (causes birth defects) in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women.

Despite the risk, dexamethasone has been given to pregnant women who are at risk of delivering a child with the congenital adrenal hyperplasia (CAH) for almost 30 years. CAH is a genetic disorder that involves the inability to appropriately metabolize certain hormones.

Female children with CAH are often more masculinized than their non-CAH counterparts, both in behavior and physiology. Sometimes the virilization extends to the genitalia with atypical clitorises and labia. High dose dexamethasone is given prenatally, as soon as the woman becomes pregnant, to ‘feminize’ the female genitalia of CAH babies. Prenatal DEX serves no other purpose but to change the appearance of the female genitalia. It neither prevents CAH nor does it promote the health of the developing fetus relative to CAH. It merely de-masculinizes female fetuses, feminizes her genitalia. Conversely, it also feminizes male genitalia.

The effective dose of DEX given from early pregnancy onward and elicits 60-100 times the normal physiological levels of cortisol. Because female sexual development happens very early in gestation, DEX is given to all women who might be carrying a female CAH child. With a previous history of delivering a CAH child, there is a 1 in 8 chance that a woman will have a second CAH child, who is female. So 7 of the 8 non-CAH babies are also exposed.

Previously, we reported animal research showing that DEX combined with common environmental endocrine exposures in early pregnancy is linked to significant reproductive abnormalities in male offspring. Moreover, the adrenal system is a critical component of our stress-response and regulates a variety of physiological functions from heart rate and blood pressure to insulin response and fat storage. Research on animals shows prenatal dexamethasone has significant adverse effects on each of these systems, many of which are likley to be transgenerational – affecting the offspring and the offspring’s ‘children’ in ways that have yet to be investigated.

The Hubris of the Baby Makers

As if dosing pregnant women with dexamethasone to somehow prevent the potential masculinization of female CAH babies without evidence or safety data isn’t bad enough, physicians who specialize in in vitro fertilization (IVF) are now also using DEX, again without sufficient evidence. One small and recent study suggests that DEX may augment ovarian response and increase follicle production for egg retrieval. There was no statistically significant improvement in fertilization, implantation or pregnancy rates. Miscarriage was not an outcome variable. There are no data about the long term safety of DEX for IVF or even any efficacy studies to support the use of DEX to prevent miscarriage. And yet, DEX is used to prevent miscarriage with IVF.

The physicians using dexamethasone have no idea if it works and appear to be operating on hunch versus hard evidence. Of course, they contend, using DEX in early pregnancy (pre-implantation through 10 weeks) couldn’t hurt and therein lay the hubris – that their talents, education and years of medical practice suffice. For these experts, no confirmatory analysis or evidence is needed to verify that their treatment protocols work. Trust us, they say.

As reported in the Atlantic, a prominent IVF specialist explains:

We tell our IVF patients that in our opinion it is by and large safe to take as prescribed, that there are no proven developmental risks to the baby [and] that side effects to the woman are infrequent, temporary in nature and reversible on proper withdrawal.” He went on, “We do not go into detail describing everything in the literature on what we consider to be safe treatments. That would be overly time consuming, impossible to accomplish thoroughly and comprehensively[,] and in my opinion [would] create unnecessary patient consternation.”

Well, of course there are no ‘proven’ risks, no one has ever done the appropriate research either for the DEX in CAH or the use of DEX in IVF. After 30 years of being used off-label for CAH and potentially thousands, if not tens of thousands of babies exposed worldwide, there are no controlled studies showing either its efficacy or its safety – no robust analyses of adverse events. This may be worse than either DES or thalidomide. A recent meta-analysis on the risks of prenatal DEX use for CAH found only four studies with marginally useful data. Most done by the same research team with a highly questionable history. Except the one study cited above, there are no studies, none, not even in animals, on the use of DEX to prevent miscarriage. Its use with IVF remains highly speculative and experimental.

Perhaps, one of the only studies on prenatal DEX worth examining was conducted in Sweden. The researchers reviewed 43 pregnancies from 1985 -1995 where prenatal DEX was used to treat CAH. What they found was troubling; an excessively high rate of severe adverse events in the DEX pregnancies versus the control group. In the prenatal dexamethasone group, researchers identified eight severe adverse events compared to only one in the control group. These included:

3 children failed to thrive during the first year
1 child with developmental delay and hypospadias (malformed male urinary tract opening)
1 child had hydrocephalus
2 girls were born small for gestational age; one was later diagnosed with mental retardation
1 child had severe mood fluctuations resulting in hospitalizations

As a result of this study, researchers in Sweden petitioned their Regional Ethics Committee to put on hold a prospective study using DEX for CAH, citing the high risk of adverse events for what is essentially an elective treatment for reproductive cosmetics. In the US, despite petitions to the Office of Human Research Protection (OPRH – the oversight body tasked with approving human subjects research and protecting research subjects) and the FDA, there has been little oversight of the use of DEX in either CAH or IVF.

In both cases, these treatments are considered experimental and their use must be fully consented to and presumably monitored by OPRH and the FDA. Neither is happening with any rigor. Indeed, the fertility specialist’s claim – that there are no proven developmental risks to the baby [and] that side effects to the woman are infrequent, temporary in nature and reversible on proper withdrawal – mirrors the unsubstantiated and dubious claims of the one research group funded continuously by NIH for the last dozen years who have failed to produce any robust or rigorous data on the topic but nevertheless continue to market the benefits of DEX, their practice and ‘research’.

Most recently, a prominent physician and researcher from UCSF has come out to state that risks do not outweigh the benefits and that “prenatal treatment of congenital adrenal hyperplasia with dexamethasone should only be done in prospective clinical research settings with institutional review board approval, and therefore is not appropriate for routine community practice.” No such review or research exists for prenatal dexamethasone and IVF.

Is Prenatal Dexamethasone Safe?

Probably not. Administering synthetic steroids during critical periods of fetal development- when physiological systems are organizing and developing – will impact system and organ functioning. Some of those effects will be seen early on and may be visible, like malformed reproductive tracts, but others will be more subtle and present as the child ages – cognitive deficits, heart disease, or cancer. Many effects will be epigenetic or transgenerational with the grandchildren suffering the consequences. We saw that with DES, we’re seeing that in animal studies with BPA and other endocrine disruptors. One has to assume, we will see the same effects with DEX given from pre-conception or early pregnancy onward. It’s just a matter of time.

Unfortunately, it may be years before the research catches up. Therefore, it is incumbent upon pregnant women educate themselves and make informed decisions.

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This article was published originally on April 15, 2013.

More recent research (2018), reiterates much of the same.

Assisted Reproductive Technologies, Birth Defects and Epigenetics

by Chandler Marrs, PhD

Published on October 30, 2013

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Assisted reproductive technologies (ART) have grown in popularity and success over the recent decade. According to the CDC, in 2011 there were 61,610 babies born via ART, representing 1% of the US newborn population, nearly doubling ART use in just one decade. ART can be a blessing for the nearly 6% of US couples struggling with fertility issues. In the 30 years since ART began, there have been over 3.5 million children conceived using ART, many of whom are now adults of reproductive age. One wonders, what long-term, transgenerational effects might exist from ART; will those conceived via an assisted reproductive technology, also require reproductive assistance? Are the rates of cancer, especially reproductive cancers and hormone dependent cancers known to be epigenetic in nature, increased? Each of these questions remains to be addressed fully, but here is what is known so far.

The Basics – What is ART?

Assisted reproductive technologies refer to the techniques used to bring sperm and egg together in order to achieve pregnancy. The methods of assisted reproductive technologies include: in vitro fertilization – embryo transfer (IVF-ET), gamete intrafallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), and frozen embryo transfer (FET). By far the most common is IVF- ET with fully 99% of couples using this method of assisted reproductive technology. IVF begins with intense hormone treatment to stimulate maternal oocyte production. Those eggs are removed and fertilized with the donor or partner’s sperm. In most cases, eggs and sperm are placed in a petri dish and allowed to mix freely. In some cases, additional manipulation is required and the sperm is injected into the egg. This is called intracytoplasmic sperm injection or ICSI. IVF plus ICSI appears to account for a large subset of the birth defects associated with IVF.

Early Indicators of Birth Defects with Assisted Reproductive Technologies

A 2007 study of California couples found that children conceived using ART, especially those conceived with ICSI, had a 35% increase in risk for birth defects compared to those conceived naturally. Most common among them were eye abnormalities, heart defects and malformations of the genitourinary tract. Other studies have linked ART to an increased risk major structural malformations of the heart, cleft lip and palate, esophogeal atresia (the esophogus dead-ends in a pouch rather than into the stomach where it should be) and anorecto atresia – (a malformed anal opening).

Among the few studies addressing birth defects and developmental anomalies post infancy, a Chinese study found an increase in observed birth defects in ART males as time progressed, compared to females and compared to those observed at birth. In fact the rate of observed birth defects doubled over the course of the 3 years. Similarly, a study looking at one year olds conceived via ART found a doubling of the rate of multiple major birth defects including chromosomal and musculoskeletal defects.

Long Term Consequences of ART

Studies looking at longer-term difficulties, whether health or developmentally related are few and have had mixed results, always ending with the caveat that it is unclear whether the assisted reproductive technology or the original infertility itself was to blame for the defect. There does seem to be a near doubling of the risk of some rare cancers children conceived via ART, but again the data sets are small and the risk of theses cancers in general is low.

A more recent study compared cardiac function between children and young adults conceived naturally versus those conceived with ART. What they found was striking. The apparently healthy individuals with no visible malformations who were conceived by ART had significant decreases in cardiac and pulmonary functioning by a number of parameters. There was marked vascular dysfunction of the systemic and pulmonary circulation, to which the authors of the study suggest may lead to premature cardiac morbidity at a rate similar to rates seen in type 1 diabetes.

ART and Imprinting Errors

A number of ART epigenetic studies published have assessed the risk or rate of what are called imprinting errors. Imprinting errors occur when genes are incorrectly silenced. A individual normally gets one active imprinted gene, either from mom or dad. When errors occur, they may get two active or two inactive copies. Children born from assisted reproductive technologies have an increased risk of imprinting errors compared to the rest of the population. The common conditions that arise include:

Beckwith – Wiedmann Syndrome – an overgrowth syndrome where children are larger than normal
Angelman Syndrome – characterized by severe developmental disability and seizures
Prader -Willi – a syndrome characterized by short stature, developmental delay, and compulsive eating

As with the some of the other birth defects observed with ART, those using ICSI – the forcible injection of the sperm into the egg, seem to proffer higher risks and seem to affect males more than females (or perhaps, as is the case with most research, it is the male offspring that are studied more frequently). Of note, the combination of ICSI and environmental endocrine disrupting chemical exposures is linked to trends in demasculization and potential sterility.

Epigenetics and Assisted Reproductive Technologies

Thus far the notion of epigenetic changes in children conceived via assisted reproductive technologies has been limited to research on the aforementioned imprinting errors, also called epimutations. Research on the broader consequences ART, particularly in general health and reproductive health is lacking. The exposure to hyper hormonal states common in many assisted reproductive technologies has the possibility of disrupting critical hormone pathways across the lifespan of the offspring and may impact his/her reproductive health in subtle, and not so subtle, ways. Some effects may not appear until much later in life and certainly there is the possibility of transgenerational changes as those observed with DES, dexamethasone and other hormone exposures during embryonic and fetal development. Additionally, as evidenced by the study on cardiac-pulmonary function, it is conceivable that many of the epigenetic effects will be functional in nature versus more obvious structural malformations. However, because ART bypasses the natural buffers in human reproduction that might have otherwise selected out for specific traits, it is difficult to disentangle native ‘deficits’ – those of the mom and dad – versus those directly linked to the procedure itself. Only time will tell what the effects of ART are on the health and functioning of subsequent generations.

Dexamethasone During Pregnancy Increases Ovarian Germ Cell Death

by Chandler Marrs, PhD

Published on October 10, 2013

3779 views

Dexamethasone or DEX, the synthetic corticosteroid that mimics the anti-inflammatory and immunosuppressant effects of endogenous cortisol, has been given to pregnant women who are at risk of delivering a child with congenital adrenal hyperplasia (CAH) for almost 30 years, despite the fact there are no data indicating either its safety or efficacy, and one study from Sweden suggesting such a high risk of adverse events and long term consequences, that the study was halted and the use of the drug was banned.

Similarly without evidence, physicians who specialize in vitro fertilization (IVF) are using DEX to prevent miscarriage. There is only one small and recent study suggesting that DEX may augment ovarian response and increase follicle production for egg retrieval. There are no studies showing improvement in fertilization, implantation or pregnancy rates, or even data showing it prevents miscarriage, its supposed purpose. Indeed, IVF physicians have embraced the myth of this miracle hormone, on perhaps no more than medical hunch.

Dexamethasone and Ovarian Germ Cells

A recently published study looked at the impact of in vitro – organ culture – exposure of fetal ovaries (obtained from recent abortions), and ovary germ cell development. What they found was Dexamethasone Induces Germ Cell Apoptosis in the Human Fetal Ovary. Remember germ cells are those that are handed down at birth from our parents that contain the genetic materials needed to form ovarian follicles (eggs) for women, sperm cells for men. We know that dexamethasone impairs genital development in males, but this is the first study to look at DEX and females – and they went right to the source, germ cell development.

Typically germs cells divide in a logical sequence that eventually results in oocytes or eggs for women or sperm cells for men. In some women and men, the cell division progresses unconventionally, as a result of epigenetic factors including the health and environmental exposures of our parents, even our grandparents. In utero exposures to medications, such as DEX, vaccines and other toxins can cause errors in germ cells. Germ cell division is very highly environmentally influenced and as such, it is not a big leap to think that fetal exposure to synthetic hormones such as DEX during germ cell division – weeks 6-20 of pregnancy, would have an impact on ovarian health. Indeed, it does.

Researchers found that when the fetal ovaries were exposed to dexamethasone in culture for only two weeks, the rate of germ cell death increased, the density or total number of germ cells decreased, as did the expression of one of the genes associated with germ cell survival. This was with only two weeks of exposure. In most cases, women at risk of having a baby with CAH are given dexamethasone continuously from nine weeks through the first trimester. Those pursuing IVF are given DEX preconception through the first 10 weeks of pregnancy, though at a reduced dose compared to CAH. In both cases, fetal exposure to dexamethasone is chronic, during the most critical period of reproductive organ development and germ cell division, a fact that seems to be missed with the purveyors of this drug.

What Happens When We Alter Germ Cell Development?

While there may be limited adverse effects in the moms given dexamethasone, their offspring and potentially even their grandchildren may have varying levels of altered reproductive and sexual development, including changes in the structure and function of the reproductive organs, but also, in the brain chemistry that supports gender identity. We don’t know, however, because there have been so few studies and so little recognition of the potential dangers associated with prenatal dexamethasone, or even with prenatal hormone exposures in general.

In male rodents, exposed to dexamethasone in utero, there are significant problems: reduced penis size, malformed genito-urinary tracts, undescended or malformed testicles and even testicular germ cell cancer. Until this publication, females, animal or human, had not been studied. The fact that they observed germ cell errors, leads one to speculate that later in life, perhaps similar to the DES daughters and granddaughters, these women too will experience the congenital uterine malformations and the complement of reproductive diseases, that include various cancers. At the very least, because of the increased rate of germ cell apoptosis – cell death – observed in the present study, the researchers speculate in utero exposure to dexamethasone will elicit a higher and earlier rate of premature ovarian failure in the offspring.

What becomes abundantly clear is that we ought to stop dosing pregnant women with drugs, especially those hormonal in nature, when we have no data supporting safety or efficacy. We ought to recognize that these substances cross the placental barrier and will affect fetal development. Given medical history over the last 70 years from DES, thalidomide and now, DEX, it is clear any changes in medical practice must be initiated by women themselves. There seems no impetus from medical science to investigate before medicating pregnant women.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

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