Prenatal Exposures Oral History Project
The “Hidden History” of Prenatal Drugs:
A conversation with June Reinisch, PhD
"There was a gigantic growth in all kinds of pharmaceuticals after World War II. Since there was this idea of the fetal placental barrier, there was the notion you could treat the mother without interfering with the baby. That went on for much longer than it should have."
June Machover Reinisch, PhD, is a psychologist who has conducted pioneering research on the behavioral and developmental effects of medications prescribed by physicians during pregnancy, particularly synthetic hormones and compounds now known as endocrine disruptors. She is also well known for her leadership of The Kinsey Institute for Research in Sex, Gender, and Reproduction at Indiana University, where she served as director from 1982 to 1993. She has published more than 100 scientific papers in such journals as Science, Nature, JAMA, American Psychologist, Hormones and Behavior, MMWR, JPSP, Archives of Internal Medicine, and the British and American Journals of Psychiatry.
Dr. Reinisch was born and raised in New York City. She received her B.Sc. in Psychology from New York University, her M.A. from Columbia University Teachers College in 1966, and her Ph.D. in developmental psychology from Columbia University.
She has developed and followed several cohorts of children affected by prenatal exposures, including, with co-investigator the well-known epidemiologist Erik Mortensen, the Prenatal Development Project (PDP) in Denmark. The PDP evaluated the developmental effects of 1959-61 pregnancy exposure to steroid hormones and psychoactive drugs, particularly synthetic progestin, corticosteroids and barbiturates. The PDP database is unique for its breadth and depth as well as its combination of prospective longitudinal and cross-sectional perspectives. Reinisch and Mortensen are now utilizing the PDP dataset to evaluate possible links between some prenatal exposures to medications of the early 1960s and outcomes in grandchildren.
In 1977, Reinisch published a study, “Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development,” demonstrating that synthetic steroid hormones, which were often given to pregnant women in the decades after the war for the ostensible prevention of miscarriage, affected the personality development of the exposed offspring. Jill Escher, nee Jill Gilbert, was one of her exposed research subjects. After Jill first discovered her prenatal exposures in 2010, found Reinisch’s 1977 study online in 2011, and realized she had been one of the study subjects, she contacted Dr. Reinisch (whom many people call "Dr. June") in 2012 as part of her quest to discover more about her drug exposures and the broader medical context in which they occurred. The conversation below took place four years later.
Interviewed by Jill Escher, June 2016
Dr. June, I would like to start with a broad perspective. What was the thinking behind the explosion in drugs for pregnancy maintenance after the 1940s? As I understand it, the first widely used synthetic drug administered to pregnant women was phenobarbital beginning in the '30s. And then synthetic drugs for sedation, anti-anxiety, morning sickness, and other things escalated in the '50s. Can you paint a picture about the thinking in those early days? I remember you telling me they viewed the placenta as a barrier and that was one of the assumptions that went into the profligate use of new chemicals.
The medications you mention were not developed just for pregnant women. There were physicians, particularly ob/gyns, who wanted to do whatever they could do to help women to either get pregnant or stay pregnant. Their treatments were experimental, that is not based on research data but on their clinical understanding of the medications and how they might help their pregnant women who were having difficulty having children. The physicians in general aren’t scientists. They're artists. They're the artists of medicine.
So they began—they had these clubs, the medical associations where they would share information, and the drug companies, of course, are always interested in selling their products. The doctors took ideas from the drug company detail men, or they came up with their own ideas, but it was not evidence-based – just based upon their own experience and sense of what worked for them.
After World War II there was a very strong desire to build the population. I think that's true of post-war eras historically. So the '50s was a time of great expansion of families. People wanted to be pregnant and have families very badly. Medicine was also growing in influence and simultaneously there was an enormous growth of new drug development.
So there was a desire by physicians and also a desire by the public for physicians to do something when people didn’t get pregnant or couldn’t maintain their pregnancies. The zeitgeist of both physicians and the public was that there must be some kind of medications that you could give to help, and people were ready. I worked with groups in both the east and west coasts where doctors were giving DES (diethylstilbestrol) and progestins to any woman who had any problems related to being pregnant. Even if you had any problems in the past—they would start with the hormones before there was any sign of a problem in the next pregnancy.
That’s what happened with my mom. She had two prior miscarriages so went in for a prophylactic hormone treatment that started even before she conceived me. But to this day she doesn’t know the drugs she was given.
When I interviewed these women after the pregnancy, they didn’t know what they took—sometimes they didn’t remember that they took anything. But I had read their records and I knew what the doctor gave them. I would say, for example, “Don't you remember taking little red pills every day?” “No.” They were so focused on being pregnant, maintaining their pregnancy, having the baby, that they had forgotten all about it, including even when they received regular hormone injections. My studies included women who had been taking injections twice a week all the way through their pregnancy. Often they too had no remembrance of it whatsoever.
Often the women weren’t even told the names of the drugs.
It's hard to believe that but it's absolutely true. Or if they were, they did not register. Your mother was not alone and it was amazing to me. We don’t know how many millions of women took DES or had regular progestin and/or estrogen pills or injections.
And all those synthetic hormone protocols were based on no data showing safety or effectiveness. The only data that now has some support for this kind of treatment is for a weak luteal phase meaning that a woman’s progesterone is low at the beginning of pregnancy. In that case it may make some sense to add natural progesterone, not synthetic progestins, and it might actually be helpful. Once the placenta is doing the work, you wouldn’t need it anymore, but that didn’t stop the physicians. The practice was completely non-physiological, a vast majority of it, and non-research based. Of course, in the early years, testing of hormone levels was not as simple, easy or relatively inexpensive as it is today.
I've seen textbooks of the era, such as the 1961 "Sterility" by Edward Tyler, advising physicians to deploy a superabundance of powerful synthetic hormone mixtures to prevent “accidents of pregnancy” or any sort of complication. When you studied me when I was eight, you were ahead of your time thinking about dysregulating developmental effects.
The textbooks don’t mention anything like that. Today everyone knows about “endocrine disruption,” but back then no one was really thinking about the effects on the fetus, unless it was something very obvious and visible at birth like the effects of thalidomide.
Could you summarize your major findings with regard to prenatal drug exposures?
Basically we have found in a series of studies evaluating offspring of exposed pregnancies both in the United States and in Europe that hormone drug exposure affects a wide spectrum of behavioral outcomes. These include dimensions of personality, cognitive abilities, gender role and sexual orientation. The effects are subtle and do not affect a child’s success in life but add a definite flavor to their way of interacting with the social and physical environment. Our most recent study which is about to be published addresses the effects of prenatal exposure to natural progesterone and sexual orientation in male and female offspring.
Our research on the effects of exposure to corticosteroid hormones was conducted with rodents and humans with the findings similar in both. Corticosteroid exposure was related to significantly lower birth weights with a higher number of “small for dates” babies in humans. Lower than expected birth weight is generally related to negative developmental outcomes.
Our work on phenobarbital revealed that young men exposed prenatally to phenobarbital exhibited significantly lower verbal intelligence scores than predicted. Lower socioeconomic status and being the offspring of an "unwanted" pregnancy increased the magnitude of the negative effects. Exposure that included the last trimester was the most detrimental.
Tell me more about all those barbiturates, why were they used?
Early on, back to the ‘30s and ‘40s, physicians had an overall belief that women were neurotic, overly emotional. I even remember going to my wonderful physician who I loved with a skin problem. He blamed it on my not being married. It turned out to be cutis laxa, and of course it had nothing to do with my social state. This was a very brilliant man but doctors often had this view of women. So when there were problems in pregnancy, they would often give women barbiturates as a tranquilizer because they believed if you were not tranquil you could lose the baby.
That was just one of the major reasons for treatment. Then it was determined that barbiturates actually help the liver to metabolize bilirubin. As a result physicians started using them, and still do, at the end of pregnancy if there was a fear of prematurity, to rev up the liver of the fetus to prevent jaundice. Barbiturates are also used prescribed in the first few weeks after premature delivery or if jaundice is noted. I believe they're still doing that. I haven’t looked it up in the last few years but certainly they were doing it several years ago.
Reinisch paper on barbiturates
In a JAMA paper, you said 22 million American pregnancies were barbiturate exposed.
Well, that was actually a conservative number.
The DES numbers seem to vary between 2 million and 5 million. A lot of that confusion I think stems from the fact that DES was put into vitamin form and sometimes administered in non-traditional ways. Do you have a sense about the DES numbers?
We tend to hear underestimates because, first of all, many doctors would not admit that they gave it once they found out the harm it was doing. Secondly, doctors don’t keep their records past 7 years. Thirdly, many women didn’t remember they took it. Fourth, when doctors died, their records often disappeared. Plus a lot of times they didn’t write prescriptions. They might not even put in the chart.
Physicians often directly gave women drugs provided by the detail men from the drug companies. The detail men hand doctors a whole bunch of free drugs, and doctors gave these out, relying on the sales pitch. It was often done in that haphazard way. The doctor just said, "Oh, this will help." Of course, the patient just wanted a baby so badly. Whatever the doctor gave them, women didn’t ask. This was the era when you did not question your doctor.
So it's impossible to know really how many people took these drugs and for how long they took them.
A 1965 medical record contained notes of some of Jill's prenatal drug exposures
I remember when I told you that the office of my mother's former obstetrician Dr. Alfred Heldfond had some of the records of her pregnancy with me on microfilm, and your reaction was something to the effect of you'd never heard of an obstetrician holding on to records that long. I have found only one other family from the 1960s that had access to some of their prenatal records.
Most doctors disposed of records on a regular basis or didn’t want to be bothered. In truth, they were concerned about being sued or, before computerization of records, it was physically very difficult to warehouse all an office’s records during a long practice.
Well, after the DES catastrophe OBs and fertility practitioners had fires and floods and managed to “lose” their records. Certainly, the Los Angeles clinic of Dr. Edward Tyler, who was my mother's fertility practitioner, had a “fire.”
Fortunately, I had his records from the era. He was very generous in sharing them with me for my research.
Right, which is part of how I found out about my exposure. What a miracle to get that information. At most, people have a little bit of hearsay from their mother. But as you indicated, the mother's information was often poorly recollected and sketchy and she didn’t even know what she was given half the time. I remember you calling the prenatal drug era a big hidden history.
Yes, a hidden history. There was a gigantic growth in all kinds of pharmaceuticals after World War II. Since there was this idea of the fetal placental barrier, there was the notion you could treat the mother without interfering with the baby. That went on for much longer than it should have.
I was always looking at the animal research to see whether there was something we should be focusing on in humans. I don’t think that the average physician really reads the medical literature and responds to it. We need to do more to make physicians cognizant of what they're doing particularly in terms of the effect on the next generation. They are not alerted to what we research scientists find.
When you started looking into these questions in the early '70s, you were a PhD student at Columbia, right?
Right. I was interested in the natural development of masculinity and femininity, and how during the normal development of males and females, the presence or absence of hormones that are made by the male testes develop the body and the brain of human males and the absence of those hormones basically are the reason why we get a female in both sexes. Both sexes start out with the same form for male and female internal and external genitalia. It's only the presence or absence of testosterone basically and a Mullerian-inhibiting substance that makes for male on one hand then a female on the other. Occasionally, you get the development of both male and female organs when testosterone is produced (forming male genitalia) and there is a lack of Mullerian-inhibiting substance (permitting the development of female internal genitalia).
Since you can't study that prenatal process directly, I became interested in what happens if you treat humans experimentally with exogenous hormones. So I was first interested in the progestins that have androgenic qualities like Norgestrel.
Why did some of those progestins have those androgenic qualities?
All these laboratory produced steroid hormones start on the same base and then radicals are added to them, and those parts of the molecules make them either androgenic or estrogenic. The drug companies want to produce medications in the cheapest way possible. And,they wanted ones that had strong progestenic action. They weren’t concerned about the other side actions these compounds might have. So Norgestrel has a very strong progestenic action. It just happens to also have some androgenic (testosterone-like) actions well.
So the females who were exposed to that were often virilized, right?
Yes, they often caused some virilization depending again on when and to what dosage the fetus was exposed. Each fetal maternal pair is unique and it's unique biochemically in the sense that whatever you add to that pair is going to affect that pair in a unique way. The placenta and fetus are going to metabolize that substance differently, and then the target tissue of the fetus is going to respond to whatever that metabolites are, and of course how much the mother is given and when it's given to the mother. It's not a one-to-one relationship. But overall in a group, you can say if you give them X substance, this is more likely to happen.
I'm interested in the sexually dimorphic brain effects of the synthetic hormones. I know that in your study in which I was a subject, you found different effects on personality based on whether we were more heavily progestin or estrogen exposed. I was in the heavily exposed progestin group. You found we had traits that varied from controls. People say, "Well, Jill, how are you different? You seem so normal. You're not autistic. You're not disabled." I try to summarize your findings by saying that we had personality differences, we were more independent, less groupish,, less need of emotional succorance.
Yes, more individualistic, more self-assured. When you look at the tests, it's more of a masculine configuration. But humans are not black and white on anything. So it's like a flavoring, I say when I lecture on this. You're more flavored. You're a little bit more chocolate than strawberry. It's the flavoring. But this is important — these temperament or personality flavors are indicative that there are more things going on biochemically. It's a red flag that there have been changes in the organism’s brain.
People, and this includes a lot of scientists, don’t understand that behavioral changes are in a sense bioassays for possible physiological changes. We can't go into humans and look at all their tissues and slice their brains up. But if people are behaving differently, that in a sense is a bioassay of other things that may be going on in the body, particularly in the brain. But people don’t want to see it that way. I don’t know if they find the idea threatening — that behavior is biological. They don’t see behavior as a flag of biological events.
They want to see something. They want to see a genetic change, something genetic or biochemical, which is asking for something way down the line. Where do you go to look for that? What if it's in the amygdala? How are you going to go in and identify that? So yes you were changed by your exposures. Behaviors reflect underlying biological events.
Many researchers are looking at animal models for behavioral differences as a consequence of certain kinds of stressful or endocrine-disrupting chemical exposures. It's sort of dismissed, right, because it's behavior instead of missing fingers or toes and arms or legs. I think there's a lot of unwarranted skepticism in the scientific community about this.
Now the field is interested in intergenerational transmission of behavioral traits, which of course I'm firmly interested in for obvious reasons.
When we first talked, back around early 2012, I asked you, when doctors were giving all these synthetic hormonal drugs to pregnant women, didn’t anybody think about the fetus' germ cells?
Oh, no. They did not.
After thalidomide there was a lot of thought about birth defects. There was a huge spate of research papers on birth defects but birth defects were defined so narrowly as to really only encompass gross anatomical differences. But no one really thought about these molecular differences on the germline or these long-term kind of behavioral neurodevelopmental components.
Yes, and now there’s new thinking about the level of genetic change that could come from exposures and experience, post-fertilization experience including biochemical or chemical effects. It’s opening up people's minds a bit to considering the effects on germ cells, then skipping a generation in a sense.
But it's remarkable to me even today, more than a half century after I and millions of others were exposed to these powerful drugs, the FDA review is so narrow it does not address germ cells at all! It is still a ten-fingers, ten-toes era. And still, very, very little concern about neurodevelopmental consequences. The drop of five or ten IQ points could be very, very significant but we hardly look at that.
Absolutely. What I think is even more important is emotional reactivity, resiliency. Changes in reactivity are even more important than a five-point drop in IQ and we are not testing for that. Exposures change temperament to some extent. If an individual‘s ability to respond to stress, the ability to respond to anxiety is altered in the wrong direction, you've changed somebody's entire life.
I know of some animal studies that find those impairments in stress response based on ancestral EDC exposure. David Crews at UT Austin published a study a few years ago, for example.
Right. What we find in with exposed monkeys, for example, is a baby monkey may look perfectly normal until later on in life it's confronted with a stressful situation and then it just falls apart. We now have an enormous number of young people who have trouble becoming independent, there’s a case to be made that this may be the result of some old exposures or early experiences.
One of my top concerns right now is the generational effects of maternal smoking.
The PDP has some data on those exposures, but it’s not perfect. Because at the time they collected the data, the original data in '59 to '61, they didn’t realize smoking was that serious. So the researchers asked less specifically about the amount of smoking than we would if we were collecting the data today. Still, we have some relevant data to analyze with regard to smoking while pregnant and the potential effects on offspring.
At least with respect to smoking, the conventional wisdom is that it does cause fetal problems. So when I talk to people about the germline in the fetuses of smoking women, I don’t get those blank stares. More like, "Oh, that makes sense. It's mutagenic." The idea that smoking, especially heavy and persistent smoking, would induce mutations or some kind of molecular havoc is not a strange concept to them. Smoking resonates with people in a way the medications don’t.
Because it's cancer-causing so right away everybody is alert to that I think. It's easier for them to understand. Doctors used to tell pregnant women to take up smoking to control appetite or for other reasons; for example, my girlfriend’s doctor used to tell her to smoke so that she would have a bowel movement. You can also find smoking recommendations in medical books of the era. This was the era when doctors decided a pregnant woman should not gain more than 25 pounds or so. But with regard to compounds understood as “medicine,” people are far less likely to think of them causing harm.
Scientifically, you should not just be interested in the direct effects of the toxic ingredients in cigarettes. But cigarettes also adversely affect the mother, the placenta. They narrow the blood vessels and the way the fetus is nourished, including oxygen. And not only nourishment but also removal of wastes from the fetus. All this goes through the tiniest of blood vessels and those capillaries are affected tremendously by cigarette smoking. So forgetting what the actual chemical might do itself to the developing brain, germ cells, and so forth, smoking also diminishes oxygen to the fetus, lowering nutrients to the fetus and limiting the excretion of waste products.
It’s stunning that we have never studied the grandchild effect of all that maternal smoking in the decades after the war. It strikes me as one of the most obvious biological questions today. I want to ask, did you ever study amphetamines? I know those were very commonly given to pregnant women in that same era.
A lot of times they were given in vitamin shots and people didn’t even know they were getting them. It would be mixed with B12, vitamin C and whatever else. I don’t think the majority of Ob/Gyns were doing it but the dandier ones were. It's not something that the poor folks got.
We talked about the socio-demographics of the synthetic hormones when we first spoke. I told you about my mother going to Dr. Edward Tyler in Los Angeles, who you knew. He only treated wealthier women who could afford his hormone treatments.
Oh, yes, I knew him well. Dr. Tyler only saw well-off patients, there was nobody poor going to his private fertility clinic. I can't talk about what was going on in the middle of the country, because I studied practices on the coasts, but my guess is that it was the same pretty much across the country. These treatments generally were prescribed to middle class, upper middle class and well-off women.
One of the early findings in autism was that the condition was found at much higher rates white upper class families. And no one could think of any biological reason for it because usually when you see these pathologies, pathologies tend to find their way down the socioeconomic ladder not up. So this was a very anomalous situation.
We need research to see if these old treatments might be a factor in the rising rates of autism and other developmental problems in grand-offspring. Smoking as well. And we should not forget the burgeoning number of over-the-counter drugs that have become available in pharmacies and supermarkets that women can unwittingly take during pregnancy based upon the belief that if it is an OTC, it must be safe!
You've seen the outcomes of many medicated pregnancies and you've, in a very scientific way, noticed deviations from the norm. I'm wondering if you could make a general statement about the risks of introducing artificial molecules into the womb. When pregnant women are entertaining risk, where do they draw the line?
That's a good question. My feeling is we know so little and the barrier between mother and fetus is so permeable, that one really wants to add nothing foreign at all if possible. And it's not just a direct effect on the fetus itself but as we were talking about before, things like caffeine and tobacco and aspirin affect the way the fetus is nourished. Aspirin, for example, makes capillaries bleed. Since the fetus is being basically kept alive through the capillaries in the placenta, you don’t want to be taking anything that affects capillary action, capillary health.
All kinds of things that would mean nothing to the adult organism or the relatively developed organism could have a negative effect on fetal development. Because if the way that the fetus is being fed and oxygenated and the way that waste is being removed is altered by a drug that could have a negative effect on the development of that organism. So even something as mild as regularly taking aspirin or Pepto-Bismol, which has the same kind of chemical in it, might have long term effects on the fetus — we just don’t know what those effects that might be.
What I always say to my women is you're developing a person who you're going to be responsible for for the rest of your life whether you like it or not. What I would think you would want is the absolutely healthiest baby you can gestate, and you have nine months plus breastfeeding in order to do this. It would seem to me that you would be willing to deny yourself basically anything in order to do the best for that child. My feeling is you want to eat very good food and take very good care of yourself while you're doing this job.
Dr. June, as somebody who has two severely autistic children, I would not wish cognitive or developmental impairment on anybody.
Nobody knows better than you do.
And I never smoked. I don’t drink. I don’t do drugs. I don’t even take medications. I'm very active. So for me to have these kids, who are so catastrophically mentally disabled, is just incredible. I’m very troubled that prenatal drugs are still given so freely with almost no review of potential long-term or generational effects. This includes synthetic hormones. One of the progestins I was exposed to, Delalutin, now sold under the brand name Makena, is very heavily used.
I have written about dangers of synthetic hormones in depth in some speciality journals and book chapters, and also published my findings in the top journals. But it seems to have little effect. One example — I’ve published data on harmful effects of prenatal corticosteroid exposure both in animals and in humans in Science, Nature, JAMA, top journals, and it seems to have little effect on medical practice. Nobody goes back into the literature – clinicians especially. It's really quite shocking that you do research, have findings showing there's something damaging, and that people should be careful. With the corticosteroids, for example, we made it very clear we should be very careful about giving them to pregnant women. It made little impression on the medical community.
Well, as someone heavily exposed to corticosteroids and other synthetic hormones in utero, I can’t thank you enough for your research. Thank you for saving my exposure records and sending them to me. Little did I know when I was 8 years old that four decades later I would finally make sense about why those researchers kept coming to my house and testing me. I still can’t believe how lucky I am to have finally learned about my past.
Well, and I want to thank you for working to make these findings on prenatal exposures more available to the public.
This interview was first published in June 2016.