Back in the 1940s, '50s and '60s, doctors prescribed a hormone called diethylstilbestrol, or DES, to millions of pregnant women in the unfounded belief it would prevent miscarriages.
Smack in the middle of this period, the deformed thalidomide babies demonstrated the terrible things that can happen when drugs are casually prescribed during pregnancy.
But the effects of DES were much more insidious. It wasn't until 1970 that doctors in Boston, where DES use was especially popular, discovered a rare vaginal cancer in young women who had been exposed to the hormone in utero.
Now comes the most definitive accounting so far of the lifetime toll on the so-called DES daughters.
A study in this week's New England Journal of Medicine tallies the risks of a dozen DES-related disorders among 4,600 women whose mothers took the hormone during pregnancy, compared to 1,900 others who weren't exposed.
For instance, DES daughters have had:
— Five times the risk of delivering a premature baby;
— Nearly four times higher risk of a second-trimester miscarriage;
— Almost four times more risk of an ectopic pregnancy.
They're also considerably more likely to be infertile, suffer a spontaneous abortion, have a stillbirth, develop a dangerous condition called preeclampsia during pregnancy, have early menopause and have early signs of uterine cancer.
Overall, the risk of breast cancer is not different from women who weren't exposed to DES. But a subgroup of DES daughters - those whose mothers started taking the hormone earlier in pregnancy and thus exposed their fetuses to a higher dose - have about twice the risk of breast cancer than non-exposed females. (In absolute terms, they have about a 4 percent risk, versus 2.3 percent among DES daughters who had lower exposures.)
Perhaps the most significant new finding is the very high incidence of reproductive problems among DES daughters who had higher exposures to the hormone.
Two out of three had preemies. Nearly 60 percent had spontaneous abortions. Forty-one percent were infertile. One in four had ectopic pregnancies or suffered preeclampsia. And nearly one in five lost a fetus during the second trimester.
The study identified women with higher DES exposures by the presence of telltale changes in vaginal tissue. However, this isn't a useful marker for increased risk for DES daughters today, because the abnormality heals as the woman ages.
In any case, except for breast and cervical cancer, most DES daughters today are beyond most of the bad outcomes associated with their prenatal exposure to the hormone. Most of them are in their 50s and 60s.
They're advised to get regular Pap smears and mammograms because of their increased risk of uterine and breast cancer.
The publication of this new study is putting DES researchers in a reflective state of mind, 40 years after the landmark 1970 paper that first revealed the problem.
Dr. Robert Hoover of the National Cancer Institute, one of the new study's authors, notes that the harm of prenatal DES exposure might never have come to light if it hadn't been for the fact that one of those harms was such a never-before-seen cancer in adolescents.
"Without a really rare tumor occurring in a really odd group of women, we would know nothing about the huge impact on health and reproductive outcomes, because it wouldn't have been brought to anyone's attention," Hoover told Shots. The subsequent miscarriages, infertility cases and other reproductive problems would have been lost in the general background rate.
Even so, it was a matter of happenstance that the connection was made in the first place.
Dr. Arthur Herbst, another study author and the lead researcher on the 1970 paper, says in a recent You Tube posting that two women whose daughters suffered the vaginal cancer asked him, "Do you think it could have been that drug I took during pregnancy?"
That set him on the trail that led to DES.
Without that sleuthing, Hoover says, DES "would have kept being used," exposing many more women and their daughters to the dangers.
As it was, nobody knows how many women were exposed, or how many DES daughters there are today. Estimates range from 3 to 10 million.
And are there risks for the daughters of DES daughters?
"There is certainly laboratory animal evidence of third-generation effects," Hoover says. "So we have been trying to put together enough granddaughters to study them as well. Thus far, we do not have enough data to say much."