The Last Word On Nothing

“There are so many women in the world, so many fresh and young and virtuous women, so many good and kind women. Why have I been cursed with women who destroy the children in their own wombs?”

So complains Hilary Mantel’s fictional version of Henry VIII – and this Sunday marks the date, 477 years ago, when Anne Boleyn paid the price for his lament.

Boleyn was the second of Henry’s six wives. Though Henry broke with the Catholic church to marry Boleyn, he had her executed on May 19, 1536, three years after she became his wife. He was frustrated with her and her inability to have a male child – something which four of Henry’s other five wives also failed to do.

Reading Mantel’s enthralling novel, “Bring up the Bodies,” which documents the souring of the marriage through the lens of Henry’s adviser, Thomas Cromwell, I couldn’t help wondering how this situation – indeed, the course of history – might have turned out differently if the sixteenth-century English court had access to modern medicine.

Clearly, Henry *could* conceive healthy children. Most historians accept that the future king Edward VI and the future queens Mary I and Elizabeth I were Henry’s legitimate children by Jane Seymour, Katherine of Aragon and Anne Boleyn, respectively. Along with a son by his mistress, Bessie Blount, then, Henry had four surviving children from at least 11 known pregnancies. Henry’s wives were clearly fertile, yet suffered repeated miscarriages.

Possible explanations for the cause of Henry’s woes – speculation, for instance, that he might have syphilis or diabetes – haven’t solved the mystery of why he had such trouble begetting healthy kids. But the fact that his many wives all suffered miscarriages implicates Henry as the culprit, says Kenneth Moise, a maternal-fetal medicine doctor and co-director of the Texas Fetal Center in Houston.

“With that many women who have that many losses, there’s something he’s doing wrong,” Moise says.

In 2010, freelance academic Kyra Kramer suggested what that something might be: a certain form of a protein that sprouts from the surface of all of our blood cells. This protein – the Kell protein – comes in dozens of different versions that, by themselves, are totally harmless. But if we’re exposed to blood from someone with a different Kell protein than our own, our body can see the different Kell protein as a foreign invader, and send antibodies – the human version of guided missiles – to seek and destroy the invader. This is more likely to happen when the invading protein is one rare version of the Kell protein – the variety that scientists call the “K antigen,” or “big K.” Ninety-one percent of Caucasians have one of the “little k” versions of the Kell protein, and only nine percent have the “big K” version.

If a woman without the big K antigen conceives a baby who has it, she’ll be exposed to big K when she gives birth to that baby. Her immune system will whip up anti-K antibodies; she’ll carry them forever after in her body. If she then conceives another child with the big K antigen, her anti-K antibodies will cross the placenta and attack the baby’s own blood cells, with fatal consequences: the oxygen-deprived baby will almost certainly die.

In a paper in the Historical Journal, Kramer and her coauthor, Catrina Banks Whitley, proposed that Henry might have carried the big K antigen, while his wives did not. If Henry’s babies inherited the big K antigen, the first of them born to any of his wives could be born healthy. But these pregnancies would sensitize their mothers to the big K antigen, and they’d miscarry any later babies who had it.

It’s a neat theory. But Moise notes one possible hole in it: Queen Mary. She wasn’t Katherine of Aragon’s first child; Katherine’s previous four children all died in the womb or soon after birth. If Henry did carry the big K antigen, he likely passed it on to one of Katherine’s first four babies, and Katherine would have developed antibodies to it, devastating her later pregnancies. Mary never would have been born.

If Henry had one copy of the gene for big K antigen and one copy of a gene for a little k antigen – if he was what geneticists call a heterozygote – Mary could have inherited the benign little k version and survived. But if Henry was a heterozygote, each of his babies had only a fifty-fifty chance of inheriting the troublesome big K antigen from him – so you’d expect half of his children to have survived. At most, one-third of them lived.

Kramer, however, who has written a book about her theory, points out that “genetics is a bit like dice … probabilities are not ironclad rules.” She herself has three daughters – though most men, including her husband, have a fifty-fifty chance of passing on a male chromosome.

Exhuming Henry and testing his genes would be the only way to prove whether Kramer is right, but no one has been willing to pay for that project yet.

If Henry and his wives were alive today, they might not have had to suffer the heartbreak of so many lost babies. We now test all pregnant women for Kell and other blood type antibodies early in pregnancy. If a woman carries antibodies to K antigen, doctors can test her fetus for anemia and transfuse her baby with blood free of big K. Between 92 and 95 percent of big K-antigen babies who receive these intrauterine transfusions survive, Moise says. Before 1963, when the first intrauterine transfusion was performed, all of these babies died.

Had more of Henry’s children lived, he might have secured an heir while still a young man, sparing his kingdom the distraction of his marital exploits and his break with the church.

As for Henry’s marriages and Anne Boleyn’s life – who knows; it’s unclear whether Henry’s tendency to grow tired of his wives had to do with their reproductive misfortunes or his tyrannical temper. Medicine can save a life, but it might not be able to appease the whims of a king.

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Image of Anne Boleyn via Wikimedia Commons.