First Trimester Ischemia as a Risk for Autism?

In the 1950s, the company, Chemie Gruenenthal, marketed a drug intended for the treatment of respiratory infections. Soon, however, they realized it worked as an effective sedative and, more importantly for our story here, as an anti-nausea drug for expectant mothers.

That drug was called Thalidomide.

Up until that time, doctors and scientists didn’t believe that drugs could cross the placental barrier and affect the developing fetus, so safety studies were particularly lax. And thus Chemie Gruenenthal, with little holding them back, was highly successful in marketing the drug worldwide, reaching 46 countries.

Miraculously, thanks to a woman named Frances Oldham Kelsey who worked as a medical officer for the FDA reviewing drug applications, Thalidomide was never marketed in the US (though some 20,000 samples did sneak in). She and her assistants were dissatisfied with the safety studies provided by Gruenenthal and continually refused the drug’s approval, much to the company’s and her supervisor’s dismays. Yet she held her ground.

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Kelsey receiving the medal for Distinguished Federal Civilian Service from President John F. Kennedy.

But throughout other countries the drug was marketed very successfully. And by 1962, reports of major birth defects and infant deaths were starting to flood in. By March of 1962, the drug was finally removed from market. But by that time, over 10,000 reports of Thalidomide-related birth defects had been reported, several thousand of whom had died shortly after birth.

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A child with shortened upper limbs due to prenatal thalidomide exposure.

The most common birth defect was limb malformations. But the second most common defect was something known as the Moebius Sequence or Syndrome. Its symptoms are facial paralysis and eye motor deficits, which are indicative of brainstem lesions or defects. It’s believed that Moebius Syndrome typically occurs due to ischemia (restricted blood supply) during the first trimester, leading to underdevelopment or even death of affected tissues. Thalidomide is known to have effects on the vascular system, which is partly why it is currently a useful anti-cancer drug.

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A young boy with Moebius Syndrome.

Another drug, Misoprostol, which is used for chemical abortions, likewise appears to affect the embryonic vascular system and also causes Moebius Syndrome. Although scientists don’t fully understand Thalidomide’s mechanisms of action, Misoprostol is a synthetic hormone– a prostaglandin agonist, which means that it activates the prostaglandin receptor, which can have antiangiogenic properties.

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Perhaps most curious of all, both Thalidomide and Misoprostol dramatically increase risk for autism. But this risk appears to be specifically linked with the presence Moebius Syndrome. Since Moebius Syndrome is typically caused by ischemia, this suggests that ischemia during this early time period of development could in fact be a major risk factor for developing autism.

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