Hostile Blood: The Forgotten History of Rh Disease and its Miraculous Cure

I never knew my blood type – or even wondered what it was – until my freshman year in college, when I donated as part of a group service project and got a wallet-sized plastic card in the mail from the New York Blood Center. The “B-” symbol displayed in large front on the back of the card meant nothing special to me; I casually mused that I’d rather have had “A+” blood to match the grade point average I spent my nights and weekends striving for. But my roommate Eri, a plainspoken 18-year-old from eastern Europe, had a dark interpretation.

“Your blood is Rh-negative,” she said. “That means you’ll die in childbirth.”

I laughed in awkward shock. The statement was so absurd and impossible that I couldn’t even bring myself to ask her what the joke was. Surely, there couldn’t be something in my healthy blood that could endanger my dream of becoming a mother. And if there was, I was certain that everyone would know and talk about the existence of this thing.

Indeed, Eri had most of her facts wrong. But I’d later learn that, for most of history, blood type did spell tragedy for women, threatening not their own lives but those of their developing and newborn babies. Blood, the substance closest to life itself with its power to feed and clean the body and fight off infection, turned mothers’ bodies into weapons against their own infants, causing stillbirths, brain damage due to a buildup of bilirubin, severe jaundice and anemia, and swelling around the organs. An estimated 10,000 infants in the U.S. alone once died each year from hemolytic disease of the newborn, once aptly described as a “Shakespearean tragedy” for the way it turns the nurturing environment of the mother’s womb into a threat to the child’s survival.

That’s all now largely a poorly remembered past. Rh-negative women like me are all but guaranteed disease-free pregnancies thanks to a miraculous little injection of Rh immune globulin, often known by its brand name RhoGAM. It’s an “anti-vaccine” that masks or mutes an immune response instead of heightening it, and – in addition to having a flawless safety record – it has been called the most cost-effective drug ever made. Behind the simplicity of this drug, though, is a remarkable story of doctors’ tireless ingenuity; tests on willing inmates in the infamous Sing Sing prison; and crucial gifts of blood plasma – in some cases, for decades – by selfless donors who sought to protect future mothers from the tragedies they’d experienced. The only threat to the cure and its worldwide availability and adoption is the same complacency that led to my own ignorance as a teenage college student nearly 20 years ago.

A Hidden Threat

First, let’s discuss the mystery of mothers’ hostile blood. While about 2 percent of people have my rare B- blood, some 15-18 percent of a given population will have an Rh-negative blood type, meaning their blood lacks the Rh protein, also called the D-antigen, found on the surface of red blood cells. While blood type has essentially no impact on health and typically only matters when coordinating transfusions to ensure donor and recipient are compatible, it becomes critically important when an Rh-negative woman prepares to have children. If her partner has an Rh-positive blood type, she may conceive an Rh-positive child. When blood of mother and child mix – a common occurrence at birth, although it may take place earlier in gestation due to a fall or other trauma – they discover they’re incompatible. That first baby is typically unaffected; but the mother’s blood becomes sensitized with antibodies, a process called alloimmunization. Forever after, her immune response is primed, ready to respond aggressively to foreign blood. Alloimmunized mothers would in the past have a first healthy child, but then lose baby after baby, devastated and mystified by their growing series of tragedies. 

For many centuries, Rh disease was just one of many unexplained causes of fetal illness and death. The first known case of Rh incompatibility was diagnosed in 1939. In its first mention of the disease in 1944, the New York Times cited the nascent hope of a cure, saying Rh factor “need not cause infant deaths and childless marriages.” Yet nearly a quarter-century later, while my grandmother was still having children, Rh incompatibility remained a disease without a treatment. 

As detailed in Julian Guthrie’s excellent book “Good Blood,” researchers in separate parts of the world began to near a cure in the late 1950s. They knew they had to neutralize the mother’s immune response before she could become sensitized by the mixing of blood. Dr. John Gorman, an Australian-born physician working in 1958 as a blood bank resident at Columbia Presbyterian Hospital in New York, found the answer in a new pathology textbook that suggested the cause of the disease might also be the cure. The presence of circulating antibodies, it suggested, “depresses and may completely inhibit the immune response to the relevant antigen.”

Teamed with American obstetrician Vincent Freda, Gorman got to work developing a treatment of antibodies that would neutralize alloimmunization – essentially, tricking the mother’s protective body into believing it did not need to produce an immune response – but not create a risk to the baby. They’d have their first chance to conduct human testing in the early 1960s, on prisoners at New York’s Sing Sing correctional facility, where some of the nation’s most infamous criminals, including the espionage-convicted couple Julius and Ethel Rosenberg and serial killer Albert Fish, had been executed. Rh-negative male inmates allowed themselves to be injected with passive antibodies in serum as well as Rh-positive cells to test whether the antibodies would prevent sensitization. The results, as Gorman put it, were “beautiful:” the serum was unmistakably and unerringly protective. The now-standard Rh immune globulin protocol, which dictates administration of a dose within 72 hours after the blood-mixing at birth, has its roots in the Sing Sing trials: the warden would not let the scientists return any sooner, for fear of allowing a prison break.

Mystery and miracle

Even as Gorman and Freda moved confidently towards production of a cure, blood kept its secrets. To this day, celebrated Rh disease researcher Dr. Kenneth Moise told me, Rh immune globulin thwarts attempts to understand how it truly works. The common theory that it coats fetal red blood cells that enters the mother’s system doesn’t explain why the cure appears to work even when the amount administered isn’t sufficient for the coating. Likewise, Moise said, the treatment appears largely effective even when administered weeks after birth. Somehow, the introduction of what are also known as “Anti-D” antibodies neutralizes or downregulates a mother’s immune response. As often with science and medicine, those in the field must make peace with mystery.

“We don’t totally understand the mechanism,” Moise said. “But these two guys were brilliant enough to come up with it, and never won the Nobel Prize – I don’t know why. But it works. And it works very effectively.”

I got my first RhoGAM injection at 28 weeks pregnant with my first child, my daughter. It was a script, a visit to the lab, and a few moments in the chair: one more chore in a seemingly endless list of prenatal tasks and tests. I received the second and last shot in the protocol after giving birth – a regimen that has proven better than 99 percent effective in preventing alloimmunization. My pregnancy with my son three years later came after the heartbreak of a miscarriage and a stillbirth, both without known cause: just some of the senseless and all-too-common tragedies of motherhood. The RhoGAM injections then took on greater meaning to me: they felt like an invisible shield, keeping my body from betraying me yet again, giving my future babies the best chance at life. 

“It’s a miracle, isn’t it,” I told the nonplussed tech administering the shot. 

What I didn’t know then that I know now is that the predecessors of the shots I received were formulated, in large part, from the blood of other heartbroken mothers who stood to gain nothing by the cure they enabled. I’d been the beneficiary of such maternal love once before. When my son Isaac was stillborn at 20 weeks, the nurses who cared for me dressed him in unimaginably tiny crocheted clothes – a colorful hat and a shirt they gently placed atop him as he laid swaddled. I can’t think or talk about those precious little items without tears as I think about the mother who made and donated them, intimately knowing the pain of infant loss and moved by love to care for strangers in their own grief.

‘Beautiful Veins’

Olive Semmler was such a mother. The Australian woman, whose story is preserved in “Good Blood,” had one healthy child before losing seven in a row in stillbirth and early infancy due to hemolytic disease. After Australia began its Rh program in 1967, collecting antibody-rich plasma to formulate Rh immune globulin, known there as Anti-D, Semmler’s alloimmunized blood became especially valuable. She’d make 500 donations before the end of her life.

Mary Taillieu of Canada, who’d lost three babies to Rh disease, would become one of the founding members of “The Rh Ladies of Winnipeg,” a cohort of 21 women who spent hours weekly donating plasma: enough to supply not only Canada but other regions of the world as well. For years, nearly every Rh-negative Canadian mother received a piece of these women through the Rh immune globulin dose, taking in their protective antibodies but also, perhaps, the love and hopes for a brighter future that suffused each donation.

“They said I had the most beautiful veins,” Taillieu, who gave plasma for 15 years, told the Toronto Star in 2016.

The treatment for Rh has been available in the United States and much of the developed world since 1968. Marianne Cummins, another indefatigable mother from Teaneck, New Jersey, negotiated with regulators for an early release of the drug, ultimately receiving the first-ever dose of RhoGAM just after giving birth to her son.

Global shortfall 

Yet more than 50 years on, an estimated half of the world’s women who need it lack access to Rh immune globulin. Treatment of Rh disease, straightforward as it is, requires consistent prenatal care that involves routine blood typing, as well as reliable and affordable access to the drug. Dr. Steven Spitalnik, a Columbia Medical Center pathologist and executive director of the World Initiative for Rh disease Eradication (WIRhE), said the celebration of RhoGAM’s 50th anniversary at Columbia was eye-opening: nearly 3 million women annually were not getting the treatment for a disease he’d believed was eradicated, a large proportion of them in the regions of South Asia and sub-Saharan Africa. Though Rh immune globulin doses are relatively inexpensive, ignorance and a lack of advocacy – particularly by health administrators who downplay its importance – contribute to the problem. A woman in Mexico seeking a dose at a public hospital may be told she has to find and purchase it on her own, Spitalnik said.

“It might cost her $50, which for you or me may not be a big deal,” he said. “But for her, it’s a big deal.”

Lack of availability also persists in regions including South America, where shortages are common, and in China, where the drug still has yet to be approved through clinical trials, despite its global acceptance, and Rh-negative women have been known to smuggle it into the country.

Structural problems won’t disappear on account of charitable contributions, and advocates acknowledge that many poorer countries of the world, where access to Rh immune globulin suffers, are beset with other pressing health crises, like malaria, that can consume interest and resources. Still, additional attention and investment could go miles to eradicate Rh disease, from sponsoring doses to funding technology, for example, that can make blood typing simple and cheap.

“We did a back-of-the-envelope calculation,” Spitalnik said. “It would be around $150 million a year to solve this problem.”

$150 million. That would buy one F-22 Raptor fighter jet, or Jeff Bezos’ pair of Gulfstream G650ER private planes. In the context of global health, for which the United States spent $12.9 billion in fiscal 2023, it’s a rounding error.

Battling complacency

In the developed world, where access to Rh immune globulin is assured, lack of accurate knowledge may fuel another threat. Dr. Jillian Baker, a Toronto-based hematologist who has published research on Rh disease, said she’s now occasionally encountering women who decline the drug on the basis of vaccine hesitancy, a larger trend on the rise since the COVID-19 pandemic. In the U.S. too, vaccine opponents are encouraging women to decline the drug in social media groups with names like “Rhogam Rebellion Truth.” 

Baker’s also troubled by the occasions in which she’s encountered medical providers who aren’t aware of the realities of Rh disease and fail to recognize the symptoms when they encounter them in newborns, or ensure the preventive shot is administered at the right time in pregnancy and post-partum. The rarity of the disease has, in this way, created its own obstacle to effective prevention. Baker’s now developing an online curriculum for health care providers that will be available from the WIRhE website.

“I’m very poor at detecting measles – I’m very poor at knowing how to treat it,” Baker said. “Because I grew up in the era of children being immunized. So I think there’s ignorance and complacency where there’s prevention.”

A continuing gift

Today, as from the first day that Rh immune globulin was formulated, the cure to Rh disease requires a gift: the plasma of an Rh-negative donor who has been alloimmunized and is producing Rh antibodies. The naturally sensitized women who donated in the early days of the drug are now largely gone. The companies that produce the drug must solicit donations from men and women who are sterile or postmenopausal and who agree to undergo a process much like that experienced by the prisoners at Sing Sing. They’re injected with small amounts of Rh-positive healthy blood until they begin to make antibodies. While this process produces no negative symptoms and risks of blood infection are low and rigorously policed, it’s time-intensive – up to a year to achieve sensitization – and requires their commitment to donate plasma regularly, up to twice per week. The gift, though, is far-reaching: Southern Blood Services estimates a single plasma donation can produce 36 doses, enough to protect 18 births.

“When I first saw it happening, my first thought was, these donors are pretty brave,” said James Cole Elliott, a Denver-based area center medical director for CSL plasma, which makes RHOPHYLAC, another Rh immune globulin product. “It is selfless.”

Blood donations, previously made by just 3% of the U.S. population, plummeted at the start of the COVID-19 pandemic. For the first time in history, the American Red Cross, declared a national blood crisis in January 2022. In July, RhoGAM maker Kedrion Biopharma announced a shortage of the drug. Restrictions in certain parts of the world around who can donate and under what circumstances can further exacerbate supply issues.

While RhoGAM’s makers have expressed confidence that supplies will stabilize, the current shortage underscores the fragility of the substance that allowed me to have three healthy children, and my Rh-negative mother to have seven. As I consider these things, I feel a surge of gratitude – and a fresh desire to contribute to the cure.

Until recently, I’d never thought much about the season after my childbearing years, and certainly never thought of that time as a special opportunity. Now, though, I feel a little eagerness for a future in which my rare and vulnerable blood can be used to shield other mothers, stabilizing their hopes for healthy children. Like the plasma donations of Olive Semmler and Mary Taillieu, and the tiny crocheted clothes made for me by the mother whose name I’ll never know, the antibodies I contribute will be part of the unbroken fabric of compassion linking those who know the joy and pain of bearing children. My instinct, as I received my early RhoGAM shots, was right: this blood connection, and the cure it wrought, is a miracle.