Prenatal exposure to anticonvulsants and psychosexual development

This is a 1999 study with intriguing results.

The authors followed-up on 243 people who were exposed to phenobarbital and/or phenytoin before they were born.

Three of them had medically and socially transitioned; two trans men (born female) and one trans woman (born male).*

Among the 147 people who they were able to speak to, the authors also found three possible cases of gender dysphoria.

One woman had had cross-gender feelings from childhood until age 21 when she became pregnant.

Another woman “did not feel very comfortable with her femininity, but had made the conscious decision to ‘to behave like a woman.'”

Finally one of the men “denied the changes his body had undergone during puberty. He claimed to have a female’s voice (although the researcher heard a male voice), he denied having facial hair (although he had a moustache), and he denied having erections.”

There were also two gay men among the people they interviewed.

The authors looked at a control group of people born at their hospital during the same time period (1957-1972). None of them had transitioned, none of them reported gender dysphoria, and none of them were gay.

In addition, the authors compared the number of trans people in their sample to the general population in the Netherlands and the difference was statistically significant.

Clearly, something is going on here.

Why hasn’t anyone followed up on this? Well, for one thing, phenobarbital and phenytoin are no longer given to pregnant women. We don’t need to worry about any possible risks from people taking them. Besides, it would be hard to find people born recently who had been exposed to phenobarbital before birth.

On the other hand, the results suggest that it may be worth looking for connections between gender dysphoria and medications mothers take during pregnancy.

The authors of the study theorized that in order to metabolize the anti-convulsants, the fetus would produce microsomal enzymes in its liver. Then, “these enzymes also catabolize steroid hormones so that the steroids cannot properly exert their action on brain and body.”

This would suggest that prenatal hormones were involved in developing gender dysphoria.

It might be, however, that the medications themselves affected the babies.  Both phenobarbital and phenytoin are known to cause fetal abnormalities.

It could also be that the medications affected the mothers’ eggs rather than affecting the baby.

If the mothers breastfeed the babies and continued to take the drugs, they might have affected the babies’ development after birth.

Another factor to consider is that phenytoin may cause babies to develop ambiguous genitals. That in turn might affect how children are raised, including the possibility of being raised as a sex different from your genetic sex. It would be useful to know if any of the people in the study had ambiguous genitals.

It’s also possible that the drugs themselves weren’t the issue here. The mothers were taking the drugs for a reason. Could the mothers have passed on genes related to epilepsy or emotional problems that also affected gender identity? Could being raised by a mother with epilepsy or emotional problems affect gender dysphoria?

In this study, one of the trans men had a mother with epilepsy; the mothers of the other trans man and the trans woman did not. It’s not clear from the article if the two non-epileptic mothers took phenobarbital for emotional problems or pregnancy-related complaints.

There’s no information given on the mothers of the three people who did not transition but had some symptoms of gender dysphoria.

This is not strong evidence of a link between epilepsy and gender dysphoria, but it might be worthwhile for someone to do a study looking at epilepsy in the families of people with gender dysphoria.

We don’t know anything about the non-epileptic mother of the trans man as the trans men did not participate in the follow-up interviews.

However, among the people the authors interviewed, cross-gender behavior was not related to parental psychiatric problems, family problems during childhood, or socioeconomic status. This should not be surprising – cross-gender behaviors are not a problem. They are also not the same thing as gender dysphoria.

Which leaves us where we started: it is possible that something about the mothers or their genes affected the children who developed gender dysphoria.

The study provides some other evidence about exposure to the medications and psychosexual development. The authors interviewed 147 people in depth and looked at other possible traits that might have been influenced if the prenatal hormones were abnormal. This group did not include the two trans men, but it did include the trans woman and the three people with some symptoms of gender dysphoria.

They did not find statistically significant differences between the people exposed to anti-convulsants and the controls in gender role behavior in childhood or adulthood, sexual orientation,** physical development during puberty, feelings about puberty, adult satisfaction with secondary sex characteristics, or experience of their first sexual activities.

In general, the overall psychosexual development of people exposed to the anti-convulsants prenatally was not different from the people who were not exposed.

They did find, however, that there were more people in the group exposed to anti-convulsants who had high cross-gender behavior scores than in the control group. In other words, the group averages were comparable, but there were more people who were very gender non-conforming in the group that had been exposed to anti-convulsants.

So did the pre-natal hormones matter? We still don’t have the answer.

It could be that the anti-convulsants only affected some babies’ hormones. It could be that they affected the hormones, but that this isn’t enough to cause gender dysphoria in most people; perhaps the environment plays a role. It could be that the hormones are irrelevant and the medications directly affected the babies or the mothers’ eggs. It could be that something about the mothers who needed to take medications was different and affected their children.

What we do know is that taking these medications was linked to developing gender dysphoria severe enough for people to transition.

It’s a result worth some new research – does exposure to other medications affect gender dysphoria? does it matter if the father is exposed to the medication? are there any links between epilepsy and gender dysphoria?

Original Article:

Prenatal exposure to anticonvulsants and psychosexual development by Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, vd Poll N, Koppe JG, Boer K. in Arch Sex Behav. 1999 Feb;28(1):31-44.



*Some details about the transitioners:

The trans woman was exposed to phenobarbital during weeks 18-40 gestational age and one of the trans men was exposed to it during weeks 36-42.  Their mothers did not have epilepsy. They authors don’t mention the dose they took, but earlier they say that mothers who didn’t have epilepsy generally took a lower dose.

The other trans man was exposed to phenobarbitol, phenytoin, and amphetamines throughout the pregnancy. His mother had epilepsy.

All three of them started hormone therapy at age 18-23 and had sex reassignment surgery at 20-25. The trans woman had identified as a girl since early childhood; the authors did not have data on the trans men.

**However for sexual orientation in males, the p-value was 0.07 which is close to statistically significant. (There were two gay men in the group exposed to anti-convulsants and none in the control group.)