DES (diethylstilbestrol) — the Useless Pregnancy Estrogen That Gave Daughters Vaginal Cancer

When the U.S. Food and Drug Administration issued its Drug Bulletin on 25 November 1971 declaring diethylstilbestrol contraindicated in pregnancy, it was retracting an indication it had blessed twenty-four years earlier for a drug that had never been shown to work — and the trigger was not a failure of efficacy but a cancer in a generation that had been exposed before birth. DES, the first orally active synthetic estrogen, was synthesized in 1938 in the Middlesex Hospital laboratory of Sir Edward Charles Dodds in London, deliberately left unpatented, and promoted from the mid-1940s by the Harvard husband-and-wife team of George and Olive Smith as a means of preventing miscarriage by “building up” placental hormones. The gap between that promise and the documented record is among the widest in pharmaceutical history: the drug did not prevent miscarriage, and it carried a harm that would not become visible for roughly two decades.

The signal arrived in April 1971, when Arthur Herbst, Howard Ulfelder, and David Poskanzer published a case-control study in The New England Journal of Medicine reporting eight cases of clear-cell adenocarcinoma of the vagina in young women aged 15 to 22 — a tumor so rare in that age group that a cluster of eight was itself an anomaly. Seven of the eight mothers had taken DES while pregnant; only one of thirty-two matched controls had. The association was overwhelming, with the odds of chance occurrence below one in one hundred thousand. The mechanism was transplacental: a drug given to the mother had reached across the placenta and altered the developing reproductive tract of the fetus, with the consequence emerging only at puberty.

The verdict is therefore plain at the outset. An estimated five to ten million Americans — pregnant women and the children born of those pregnancies — were exposed to DES between roughly 1940 and 1971 on the strength of an indication that controlled trials had already shown to be useless. As early as 1953, William Dieckmann’s randomized, double-blind study at the University of Chicago Lying-In Hospital had demonstrated that DES did not reduce miscarriage, premature birth, or neonatal death; prescribing continued for eighteen more years regardless. The drug was not so much a wonder therapy that went wrong as an unproven one that was never stopped.

What remains is a two-generation injury with a long tail. DES daughters carry roughly forty times the baseline risk of clear-cell adenocarcinoma, develop it at a rate near 1 in 1,000, and face elevated rates of infertility, ectopic pregnancy, premature delivery, and breast cancer; DES sons and even a third generation have shown reproductive anomalies. The episode became the founding case study of the transplacental carcinogen and a standing rebuke to the idea that a drug’s safety can be judged only in the patient who swallows it.

Phenformin (DBI) — the “Imminent Hazard” Diabetes Pill Banned in 1977, Half Its Victims Dead

When Joseph Califano, Secretary of Health, Education and Welfare, signed the order suspending phenformin on 25 July 1977, he was invoking a power Congress had granted the Food and Drug Administration fifteen years earlier and which no official had ever used: the declaration that an approved medicine was an “imminent hazard to the public health.” Phenformin (phenethylbiguanide), synthesized in 1957 by a team including Seymour Shapiro at the U.S. Vitamin Corporation and marketed in the United States from 1959 by Ciba-Geigy as DBI, had been prescribed to control adult-onset diabetes for nearly two decades. It was withdrawn not because it failed to lower blood sugar — it did that adequately — but because it could quietly poison the body with lactic acid, a complication that killed roughly one of every two patients it reached.

The gap between the promise and the harm was the gap between a surrogate benefit and a survival outcome. Phenformin reliably reduced glycemia, the number physicians could see on a chart; what it did not reliably do was keep patients alive. The biguanide’s mechanism — pushing cellular metabolism toward anaerobic glycolysis — produced excess lactate, and in patients with even modest kidney or heart impairment that lactate could accumulate into a metabolic catastrophe. Phenformin-associated lactic acidosis ran at roughly 40 to 64 cases per 100,000 patient-years, and once it occurred it was fatal in approximately half of cases. The drug treated a chronic disease by trading a visible, manageable problem for an occasional, lethal one.

The verdict was therefore plain long before the suspension. As early as 1959 — the same year U.S. marketing began — the literature linked biguanides to lactic acidosis. In 1971 the federally funded University Group Diabetes Program (UGDP) terminated its phenformin arm after finding excess total and cardiovascular mortality, roughly double that of the placebo and insulin groups combined. By October 1976 the FDA’s own Endocrinology and Metabolism Advisory Committee had recommended removal. The harm sat in the published record for years while ~385,000 Americans were still taking the drug in 1977.

What forced the cord was not the agency but a consumer group and a lawyer’s petition. Ralph Nader’s Health Research Group petitioned for suspension on 22 April 1977; Califano acted in July; the drug was off the U.S. market by 15 November 1978. The episode became the founding precedent for emergency drug suspension, the cautionary prologue to its safer sister biguanide metformin, and the textbook case of how a medicine can be effective on the metric it was sold on and still be a net killer.