Tag: postdoctoral researcher

A Genetic Snapshot Could Predict Preterm Birth

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This article was originally published by Knowable Magazine.

For expectant parents, pregnancy can be a time filled with joyful anticipation: hearing the beating of a tiny heart, watching the fetus wiggling through the black-and-white blur of an ultrasound, feeling the jostling of a little being in the belly as it swells.

But for many, pregnancy also comes with serious health issues that can endanger both parent and child. In May, for example, the U.S. Olympic sprinter Tori Bowie died while in labor in her eighth month of pregnancy. Potential factors contributing to her death included complications of preeclampsia, a pregnancy-specific disorder associated with high blood pressure. Preeclampsia occurs in an estimated 4.6 percent of pregnancies globally. Left untreated, it can lead to serious problems such as seizures, coma, and organ damage.

Preeclampsia and preterm birth are relatively common conditions that can put both the mother and her baby at risk of health issues before and after birth. But doctors don’t have a good way to determine whether an individual will develop one of these complications, says Thomas McElrath, an ob-gyn at Brigham and Women’s Hospital, in Boston. Currently, physicians primarily look to a woman’s prior pregnancies, medical history, and factors such as age and ethnicity to determine her risk. These measures are useful but limited, and may fail to identify problems early enough to enable effective treatment, McElrath says. “They’re not as precise as I think most of us, as clinicians, would really want.”

That may soon change. Scientists are learning that free-floating bits of genetic material found in a pregnant person’s blood may offer a way to detect complications such as preeclampsia and preterm birth—although some experts caution that it’s too early to determine how useful these tests will be in the clinic. In the meantime, the tests are providing researchers with a new way to unravel the underlying biology of these inscrutable ailments.

All of us carry bits of our own genetic material—both DNA and its more evanescent cousin, RNA—around in our bloodstreams. During pregnancy, these free-floating fragments, known as cell-free DNA and RNA, are also released from the developing fetus into the mother’s blood, primarily via the placenta. For more than a decade, clinicians have used cell-free DNA from blood to screen the fetus for genetic abnormalities.

But DNA provides a largely static view of the genetic content within our cells. RNA gives a snapshot of which genes are turned on or off at a specific point in time. Because gene activity varies across cells and over time, researchers realized that they could use RNA to glean a more dynamic view of the changes that occur within the mother’s body during pregnancy. RNA enables scientists to look beyond the fixed genotype to factors that change over the course of pregnancy such as prenatal complications, says Mira Moufarrej, a postdoctoral researcher at Stanford University who co-authored a paper in the 2023 Annual Review of Biomedical Data Science on noninvasive prenatal testing with circulating RNA and DNA.

Read: The pregnancy risk that doctors won’t mention

To screen for possible complications, scientists have been looking at cell-free RNA in pregnant women’s blood that originates from both mother and child. Some of the earliest studies of this kind emerged in the early 2000s. In 2003, for example, Dennis Lo, a chemical pathologist at the Chinese University of Hong Kong, and his colleagues reported that in a study of 22 pregnant women, a specific RNA released from the placenta was much more abundant during the third trimester in those who had preeclampsia than in those who did not. Over the years, Lo’s group and others have looked at broader changes in RNA during pregnancy in larger groups of people.

In a 2018 study, Moufarrej, who was then a doctoral student; her adviser Stephen Quake, a biophysicist at Stanford University; and colleagues reported that cell-free RNA could help determine when labor would occur. The researchers recruited 38 pregnant women in the United States known to be at risk of preterm birth, and then drew a blood sample from each. By comparing cell-free RNA in those who eventually delivered prematurely with that in those who gave birth at full term, they were able to identify a set of RNAs that appeared up to two months prior to labor that could pinpoint about 80 percent of premature births.

That proof-of-concept investigation spurred the researchers to look further and examine whether cell-free RNA could also predict preeclampsia. Other groups had previously reported RNA-based signatures of preeclampsia—in 2020, for instance, scientists working with the California-based biotech company Illumina reported dozens of RNA transcripts that were unique to a small cohort of pregnant women with the condition. But Moufarrej, Quake, and their colleagues wanted to track RNA changes throughout pregnancy to see whether it might be possible to identify people at risk of preeclampsia during early pregnancy, before symptoms began.

In a study published in 2022, the researchers recruited several dozen mothers at heightened risk of preeclampsia and drew blood from them four times: at or before 12 weeks, in weeks 13 to 20, at or after 23 weeks, and after birth. Afterward, the researchers compared cell-free RNA for women who indeed developed preeclampsia against that of those who did not. The team identified RNAs corresponding to 544 genes whose activity differed in those who developed preeclampsia and those who did not. (The study did not differentiate between maternal and fetal RNA, but because the majority of cell-free RNA in a pregnant person’s blood is their own, Moufarrej says that most of these RNAs are likely maternal in origin.)

Then, using a computer algorithm, the researchers developed a test based on 18 genes measured prior to 16 weeks of pregnancy that could be used to predict a woman’s risk of developing preeclampsia months later. The test correctly identified all of the women who would later develop preeclampsia—and, equally important, all of the women who the test predicted wouldn’t develop preeclampsia did in fact escape the disease. (About a quarter of the women who were predicted to develop preeclampsia did not get the disease.) The same 18-gene panel also correctly predicted most cases of preeclampsia in two other groups totaling 118 women.

The team also took a closer look at which tissues the RNA of interest originated from. This included the usual suspects, such as the lining of the blood vessels (also known as the endothelium), which scientists already know is associated with preeclampsia, as well as other, more unexpected sources, such as the nervous and muscular systems. The authors note that, in the future, this information could be used both to understand how preeclampsia affects different parts of the body and to assess which organs are at highest risk of damage in a particular patient.

According to Quake, studies like these from both his team and others are starting to reveal the diversity of changes throughout the body that contribute to pregnancy complications—and providing evidence for something that clinicians and researchers have long suspected: that both preeclampsia and preterm birth are conditions with a range of underlying causes and outcomes. “There are now strong indications that you should be defining multiple subtypes of preeclampsia and preterm birth with molecular signatures,” says Quake. “That could really transform the way physicians approach the disease.”

Research teams elsewhere are also looking at other pregnancy complications such as reduced fetal growth, which can cause infants to be at higher risk of problems such as low blood sugar and a reduced ability to fight infections. Some of these tests are now being validated in large studies, while others are still in the early days of development.

RNA-based tests for both preeclampsia and preterm-birth risk are inching their way toward the clinic. Mirvie, a company co-founded by Quake in South San Francisco, is focused on developing both. Last year, the company published a study of a preterm-birth test with hundreds of pregnant individuals as well as one on a preeclampsia test with samples from more than 1,000 women. Both studies had promising results. The company is now in the middle of an even larger study of the preeclampsia test that will include 10,000 pregnancies, Quake says. (Quake and Moufarrej are both shareholders of Mirvie.)

Cell-free RNA-based tests for preeclampsia are leading the way, says McElrath, likely because preterm birth has more subtypes and more potential causes—including carrying multiples, chronic health conditions such as diabetes, and preeclampsia—which make it a more complicated issue to address. (McElrath is involved in validating Mirvie’s tests; he serves as a scientific adviser to the company and has a financial stake in it.)

Read: Childbirth is no fun. But an extremely fast birth can be worse.

Still, questions about these tests remain. An important next step, says Moufarrej, is determining what’s behind the RNA changes associated with a heightened risk for these pregnancy complications. All of the studies conducted to date have been correlative—linking patterns in RNA with risk—but to provide effective treatment, it will be important to determine the cause of these changes, she adds. Another open question is how important maternal versus fetal RNAs are to determining the risk of pregnancy complications. To date, most studies have not distinguished between these two sources. “This remains an active area of investigation,” McElrath says.

Erik Sistermans, a human geneticist at Amsterdam UMC, says that although researchers can learn a lot from cell-free RNA, it’s still too early to judge what the power of these RNA-based tests will be in clinical practice. He notes that he and other researchers are also investigating the possibility of using cell-free DNA to determine the risk of pregnancy complications such as preeclampsia. For example, some groups are looking at chemical modifications to DNA known as epigenetic changes, which occur in response to age, environment, and other factors.

Yalda Afshar, a maternal- and fetal-medicine physician at UCLA, agrees that it’s still unclear whether these tests will provide benefits not available from existing screening methods such as looking for the presence of risk factors. For these screening tests to truly benefit patients, clinicians will first need to understand the underlying biology of these complications—and have effective treatments to offer patients found to be at risk, she adds. (Afshar is an unpaid consultant for Mirvie.)

There are also ethical questions to consider. Screening tests provide only an estimate of risk, not a definitive diagnosis, Sistermans notes. Before these tests are rolled out to the public, it will be crucial to consider how best to communicate test results, and what next steps to take for individuals who are identified as being in a high-risk category, he says. For preeclampsia, low-dose aspirin can help prevent or delay its onset, while the hormone progesterone may help prevent some cases of preterm birth. But every additional test added to a prenatal screen makes decisions more complicated and potentially stressful for pregnant women. “You shouldn’t underestimate the amount of anxiety these kinds of tests may cause,” Sistermans says.

Still, researchers are optimistic about the future of cell-free RNA-based tests. The tests for preeclampsia are already more accurate than currently available tests for the condition, according to McElrath. And if researchers succeed in predicting other complications, he adds, future patients will benefit not just from additional information about their pregnancies, but also from the opportunity to receive more personalized care. “Once we start to see success in early preeclampsia prediction,” McElrath says, “it will quickly spread out from there.”

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Diana Kwon

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August 26, 2023
America’s Most Popular Drug Has a Puzzling Side Effect. We Finally Know Why.

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Statins, one of the most extensively studied drugs on the planet, taken by tens of millions of Americans alone, have long had a perplexing side effect. Many patients—some 5 percent in clinical trials, and up to 30 percent in observational studies—experience sore and achy muscles, especially in the upper arms and legs. A much smaller proportion, less than 1 percent, develop muscle weakness or myopathy severe enough that they find it hard to “climb stairs, get up from a sofa, get up from the toilet,” says Robert Rosenson, a cardiologist at Mount Sinai. He’s had patients fall on the street because they couldn’t lift their leg over a curb.

But why should an anticholesterol drug weaken muscles in the arms and legs? Recently, two groups of scientists stumbled upon an answer. They didn’t set out to study statins. They weren’t studying cholesterol at all. They were hunting for genes behind a rare disease called limb girdle muscle dystrophy, in which muscles of the upper arms and legs—sound familiar?—become weak and waste away. After both teams tracked the disease through a handful of families in the U.S. and a Bedouin family in Israel, their suspicions separately landed on mutations in a gene encoding a particularly intriguing enzyme.

The enzyme is known as HMG-CoA reductase, and to doctors, it is not obscure. It is, in fact, the very enzyme that statins block in the process of halting cholesterol production. And so, the answers to two mysteries suddenly became clear at once: Dysfunction in this enzyme causes muscle weakness from both limb girdle muscular dystrophy and statins.

This connection between a rare disease and a common drug stunned the researchers. “It seemed too good to be true,” says Joel Morales-Rosado, a pathologist who worked on one of the studies as a postdoctoral researcher at the Mayo Clinic. “One of the first things you learn in medical school is association between statins and myopathy.” Now the answer as to why— along with a potential treatment for it—has emerged from the DNA of just a few patients living with a seemingly unrelated genetic disease.

The first patient the Mayo team studied had been showing signs of limb girdle muscular dystrophy since he was a child, and his symptoms worsened over time until he lost the ability to walk or breathe with ease. (The disease can also affect large muscles in the torso.) Now in his 30s, he wanted to know the genetic cause of his disease before having children and potentially passing it on to them. His two brothers had the disease as well. So the team looked for genes in which all three brothers had mutations in both copies, which is how they zeroed in on the gene for HMG-CoA reductase.

Six more patients from four other families confirmed the link. They too all had mutations in the same gene, and they too were all diagnosed with some degree of limb girdle muscular dystrophy. (Interestingly, for reasons we don’t entirely understand, they all have normal or low cholesterol.)

Unbeknownst to the Mayo team, a group of researchers halfway around the world was already studying a large Bedouin family with a history of limb girdle muscular dystrophy. This family also carried mutations in the gene encoding HMG-CoA reductase. Those afflicted began experiencing minor symptoms in their 30s, such as muscle cramps, that worsened over time. The oldest family members, in their late 40s or 50s, had lost all movement in their arms and legs. One bedridden woman had to be ventilated full-time through a hole in her windpipe. Another had died in their mid-50s, Ohad Birk, a geneticist and doctor at Ben-Gurion University of the Negev, in Israel, told me. When his team saw that this family had the mutations in HMG-CoA reductase, they too immediately recognized the potential link to statins.

This pair of studies in the U.S. and Israel “really strongly suggests” that statins cause muscle damage via the same HMG-CoA reductase pathway, says Andrew Mammen, a neurologist at the National Institutes of Health who was not involved in either study. The enzyme’s role had been suspected, he told me, but “it had never been proven, especially in humans.” (Questions still remain, however. The enzyme, for example, is found in tissues throughout the body, so why do these common side effects show up in muscles specifically?) Rosenson, at Mount Sinai, wondered if variations in this gene could explain why statins don’t affect everyone the same. Perhaps patients who suffer particularly severe muscle side effects already have less functional versions of the enzyme, which becomes problematic only when they start taking statins, which reduce its function even further. This research might end up concretely improving the life of at least some of the patients most severely affected by statins.

That’s because Birk’s team in Israel did not stop at simply identifying the mutation. For two decades, he and his colleagues have been studying genetic disorders in this Bedouin community in the Negev and developing genetic tests so parents can avoid passing them on to their children. (Cousin marriages are traditional there, and when two parents are related, they are more likely to carry and pass on the same mutation to a child.) With limb girdle muscular dystrophy, his team went one step further than usual: They found a drug to treat it.

This drug, called mevalonolactone, allows muscle cells to function more normally even without the HMG-CoA reductase enzyme. Birk’s team first tested it in mice given doses of statins high enough to weaken their limbs; those also given mevalonolactone continued to crawl and even hang upside down on a wire just fine. They seemed to suffer no ill effects. When that experimental drug was given to the Bedouin woman bedridden with limb girdle muscular dystrophy, she also started regaining control of her arms and legs. She could eventually lift her arm, sit up by herself, raise her knees, and even feed her grandchild on her own. It was a dramatic improvement. Birk told me he has since heard about dozens of patients with limb girdle muscular dystrophy around the world who may benefit from this experimental drug.

Mammen and others think the drug could help a small subset of patients who take statins as well. However, the majority of patients—those with relatively minor pains or weaknesses that go away after they switch statins or have their dosage reduced—probably don’t need this new treatment. It probably even undermines the whole point of taking statins: Mevalonolactone eventually gets turned into cholesterol in the body, so “you’re basically supplying the building blocks for making more cholesterol,” Mammen said. But for some people, numbering in the thousands, severe muscle weakness does not go away even after they stop taking statins. These patients have developed antibodies to HMG-CoA reductase, which Mammen suspects continue to bind and disable the enzyme.

Mammen is eager for these patients to try mevalonolactone, and he’s been in touch with Birk, who unfortunately doesn’t have enough of the drug to share. In fact, he doesn’t even have enough to treat all of the other family members in Israel who are clamoring for it. “We’re not a factory. We’re a research lab,” Birk told me. Mevalonolactone is available as a research chemical, but that’s not pure and safe enough for human consumption. Birk’s graduate student Yuval Yogev had to manufacture the drug himself by genetically engineering bacteria to make mevalonolactone, which he then painstakingly purified. Making a drug to this standard is a huge amount of work, even for commercial labs. Birk is looking for a pharmaceutical company that could manufacture the drug at scale—for both patients with limb girdle muscular dystrophy and those with the most severe forms of statin-associated muscle damage.

Back in 1980, the very first person to receive an experimental dose of statins suffered muscle weakness so severe, she could not walk. (She had been given an extremely high dose.) Forty years later, muscle pain and weakness are still common reasons patients quit these very effective drugs. This recent breakthrough is finally pointing researchers toward a better understanding of statins’ toll on muscles, even if they still can’t fix it for everyone.

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Sarah Zhang

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June 27, 2023
A Teen Gender-Care Debate Is Spreading Across Europe

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As Republicans across the U.S. intensify their efforts to legislate against transgender rights, they are finding aid and comfort in an unlikely place: Western Europe, where governments and medical authorities in at least five countries that once led the way on gender-affirming treatments for children and adolescents are now reversing course, arguing that the science undergirding these treatments is unproven, and their benefits unclear.

The about-face by these countries concerns the so-called Dutch protocol, which has for at least a decade been viewed by many clinicians as the gold-standard approach to care for children and teenagers with gender dysphoria. Kids on the protocol are given medical and mental-health assessments; some go on to take medicines that block their natural puberty and, when they’re older, receive cross-sex hormones and eventually surgery. But in Finland, Sweden, France, Norway, and the U.K., scientists and public-health officials are warning that, for some young people, these interventions may do more harm than good.

European health authorities are not reversing themselves on broader issues of trans rights, particularly for adults. But this turn against the Dutch protocol has inflamed activists and politicians in the United States. Republicans who have worked to ban its recommended treatments claim that the shifts in Europe prove they’re right. Their opponents argue that any doubts at all about the protocol, raised in any country whatsoever, are simply out of step with settled science: They point to broad endorsements by the American Medical Association, the American Psychiatric Association, and the American Academy of Pediatrics, among other groups; and they assert that when it comes to the lifesaving nature of gender-affirming care, “doctors agree.”

But doctors do not agree, particularly in Europe, where no treatments have been banned but a genuine debate is unfurling in this field. In Finland, for example, new treatment guidelines put out in 2020 advised against the use of puberty-blocking drugs and other medical interventions as a first line of care for teens with adolescent-onset dysphoria. Sweden’s National Board of Health and Welfare followed suit in 2022, announcing that such treatments should be given only under exceptional circumstances or in a research context. Shortly after that, the National Academy of Medicine in France recommended la plus grande réserve in the use of puberty blockers. Just last month, a national investigatory board in Norway expressed concerns about the treatment. And the U.K.’s only national gender clinic for children, the Tavistock, has been ordered to close its doors after a government-commissioned report found, among other problems, that its Dutch-protocol-based approach to treatment lacked sufficient evidence.

These changes in Europe have so far been fairly localized: Health authorities in many countries on the continent—among them Austria, Denmark, Germany, Italy, and Spain—have neither subjected the Dutch approach to formal scrutiny nor advised against its use. Yet questions about the protocol seem to be spreading. At the end of March, for example, a Belgian TV report described a 42-fold increase in patients at a leading gender clinic in Ghent and raised questions about the right approach to care. Doubts about the protocol have even come to the country that invented it, at the Center of Expertise on Gender Dysphoria in Amsterdam. “Until I began noticing the developments in other EU countries and started reading the scientific literature myself, I too thought that the Dutch gender care was very careful and evidence-based,” Jilles Smids, a postdoctoral researcher in medical ethics at Erasmus University in the Netherlands, told me via email. “But now I don’t think that any more.”

Kirsten Visser, a Netherlands-based advocate and consultant for parents of trans teens, says her own son, Sietse, started receiving “definitely lifesaving” care at the Amsterdam center in 2012, at the age of 11. Around the time that Sietse showed up at the clinic, the Dutch protocol was becoming established internationally, largely through the work of a child and adolescent psychiatrist there named Annelou de Vries.

After completing a Ph.D. on gender dysphoria in Dutch adolescents, de Vries published two seminal papers with the clinical psychologist Peggy Cohen-Kettenis and other colleagues, in 2011 and 2014. The former looked at the psychological effects of puberty suppression on 70 young people over a period of two years, on average; the latter tracked outcomes for 55 of those people who had gone on to receive gender-reassignment surgery, over an average of six years. Taken together, the studies found that the teens showed fewer symptoms of depression after having their puberty suppressed, as well as a decrease in behavioral and emotional problems; and that the ones who went on to take gender-affirming hormones and have surgery grew into “well-functioning young adults.” De Vries’s expertise has since been widely recognized within the field: She served as a co-lead on the revision of the adolescent section of care guidelines recently published by the World Professional Association for Transgender Health, and is now president-elect of the European equivalent, EPATH.

But in the years after her two studies were released, research done in other European countries led to concerns about their relevance. In 2015, for example, Finnish researchers described a phenomenon that “called for clinical attention,” as they put it: More children were reporting gender dysphoria, and a greater proportion of them had been assigned female at birth. The fact that three-quarters of those Finnish teens had been diagnosed with separate and severe psychiatric conditions appeared to be at odds with the data from the Netherlands, the paper argued. The Dutch studies had found that just one-third of adolescents with gender dysphoria experienced other psychiatric issues, suggesting they were in far better mental health.

In Sweden, too, clinicians grew alarmed by the sudden increase in the number of teenagers seeking gender care. Mikael Landén, a professor of psychiatry at the University of Gothenburg, told me that this population has increased 17-fold since 2010. One explanation for that change—that more open-minded attitudes around gender have emboldened kids to seek the help they need—just doesn’t ring true to him. He’d studied those views in his early work, he said, and found that, on the whole, Swedish attitudes toward transgender people have been very positive for a long time.

When the government asked Landén and a group of other scientists to write an evidence-based review of hormone-based treatments for young people, their verdict, after two years of study, was expressed definitively: The original research findings from de Vries were outdated, and do not necessarily apply to the group of teens who have been coming forward in more recent years. The Dutch protocol had been “a valuable contribution,” he told me, and “it was reasonable to start using it” in Sweden. But times had changed, and so had the research literature. In 2021, for instance, a team based at the U.K.’s Tavistock clinic published research showing no detectable improvements in the mental health of youngsters who had been put on puberty blockers and followed for up to three years.

Read: The war on trans kids is totally unconstitutional

De Vries acknowledged some concerns about the research when we spoke in February. “Our early outcomes studies were really from another time and comprised small samples,” she told me, and they looked only at trans youth who had experienced gender dysphoria from childhood. She granted that there is some research to suggest that kids who don’t arrive at the clinic until they’re older are worse off, psychologically, than their younger peers; but she also said her team has run studies including 16-year-olds, and that their findings were “not worrisome.” She agrees that other researchers have not replicated the long-term follow-up research on kids who went through the Dutch protocol, but she pointed out that the short-term benefits of such treatment have indeed been seen in other studies. Research conducted in the U.S., and published earlier this year, found that a group of 315 trans and nonbinary youth were on average less depressed and anxious, and better-functioning, after two years of hormonal treatment.

In the meantime, de Vries and her colleagues have urged clinicians in other countries to do more of their own investigation, in part because the youngsters who receive care at gender clinics in the Netherlands seem to be in comparatively good mental health from the get-go. It’s not yet clear, she told me, that studies of this group will be applicable to youth in other countries. “Every doctor or psychologist who is involved in transgender care should feel the obligation to do a good pre- and post-test,” one of de Vries’s co-authors on the 2011 and 2014 studies said to a Dutch newspaper in 2021. “The rest of the world is blindly adopting our research.”

De Vries is now working on a research project, funded by an $864,000 grant, that will try to answer newly forming doubts about the Dutch protocol. Her proposal for the grant, filed in 2021, described its subject as a “once so welcomed but now sharp[ly] criticized approach.”

That such criticisms are becoming mainstream even in her own country is itself a startling development. After all, the Netherlands has long been at the vanguard of progressive health-care practices. When the Dutch approach to transgender care for adults first started taking shape during the 1970s (many years before the protocol for kids would be established), the country’s politics were dominated by a steadfast opposition to taboos. James Kennedy, an American-born professor of modern Dutch history at Utrecht University, has described this as the country’s “compassionate culture”: In a radical departure from its traditional Christian conservatism, long-standing policies were being spurned; and even touchy subjects such as death and sex were made the subject of broad public-policy debates. Sex work, for example, was widely tolerated, then legalized in 2000. Similarly, the Royal Dutch Medical Association offered formal guidelines for the practice of euthanasia in the 1980s, and a corresponding national law—one of the world’s first—codified the rules in 2002.

Against this backdrop of openness, in which doctors were seen as authoritative figures who were well equipped to decide what was best for their patients, one of the first dedicated clinics for transgender people was established in Amsterdam in 1972. It offered an array of services—blood tests, hormone therapy, and surgeries—to trans adults. According to a recent book by the historian Alex Bakker, Dutch surgeons, some of them inspired by their Christian beliefs, developed techniques that would reduce patients’ psychological suffering. “Helping those in need trumped ‘taboos’ about the sanctity of life or fixed gender roles,” Kennedy told me. The Dutch protocol for treating gender dysphoria in children, as established in the 1990s, reflected a further extension of this philosophy, aiming to smooth adult transitions by intervening early.

Read: Take detransitioners seriously

Nevertheless, in December, a journalist named Jan Kuitenbrouwer and a sociologist named Peter Vasterman published an opinion piece in a leading daily newspaper, NRC, that took aim at the Dutch protocol and its “shaky” scientific foundations, and alluded to the international scrutiny of the past few years. “It is remarkable that the media in our neighboring countries report extensively on this reconsideration,” the article said, “but the Dutch hardly ever do.” Like critics elsewhere, Kuitenbrouwer and Vasterman pointed to the rising numbers of children seeking care, from 60 to 1,600 in the Netherlands across a dozen years, and the unaccounted rise in those assigned female at birth; and they suggested that this new generation of people seeking treatment is not analogous to those included in the studies conducted by de Vries a decade ago. De Vries and some colleagues countered that their more recent research addresses this concern. “Scientific evaluation has always been an integral part of this challenging model of care, where young people make early decisions about medical interventions with lifelong implications,” they wrote in the same newspaper.

Also in December, a clinical psychologist at Radboud University’s gender clinic in Nijmegen named Chris Verhaak told a different Dutch outlet that puberty blockers affect children’s bones, and maybe also their brain development. “It is not nothing,” she said. Verhaak is currently running a government-funded study to understand the source and nature of the increase in the number of patients. (Results are due to be presented to the Dutch House of Representatives this year.) In another interview that month, she said that for up to half of cases, the gains in suppressing puberty are not clear. “I worry about that,” she told the newsweekly De Groene Amsterdammer. “Especially because we also experience enormous pressure to provide these puberty inhibitors as quickly as possible.”

Verhaak’s comments in particular sparked dismay among trans groups, which saw them as promoting destructive narratives about social contagion. Verhaak and her direct collaborators say that they are no longer speaking to the media until their study is released, but Hedi Claahsen, a professor and principal clinician on the Radboud center’s gender team, told me that practitioners are cautious and follow national guidelines. When I asked if her center’s approach differed from the one used in Amsterdam, she told me, “No clinic is exactly the same.” Individual providers, who are working at different institutions, may end up providing care that reflects “a different vision.”

Another, more significant round of criticism arrived at the end of February, when another widely read Dutch newspaper, de Volkskrant, published a 5,000-word article under a headline reading: “The treatment of transgender youth in the Netherlands was praised. Now the criticism of ‘the Dutch approach’ is growing.” The authors spoke with Iris, a 22-year-old woman who spent five years on testosterone and had a double mastectomy that she now regrets; they pointed to a new population of kids assigned female at birth seeking care only in their teens; and they noted reservations about the protocol in Finland and Sweden. “Is the ‘Dutch approach’ still the way to go?” the story asked.

The article prompted debate on Twitter, where Michiel Verkoulen, a health economist working with the government of the Netherlands to address the long-standing problem of ever-expanding waiting lists and their impact on young people’s mental health, accused the Dutch protocol’s critics of ignoring what he described as the elephant in the room. “What to do with the people for whom transgender care is critical?” he asked. “You can put every research aside, keep asking for more, and argue that diagnostics and treatments should be stricter … But the question remains: What then?”

“In the Netherlands there are more and more people saying that gender diversity is woke and it’s nonsense and it’s bullshit,” Visser, the consultant for parents of trans teens, told me. Sam van den Berg, a spokesperson for an Utrecht-based trans-rights organization called Transvisie, argued that this debate does not need to happen. The quality of care for children with gender dysphoria is better in the Netherlands than almost anywhere else, she said. “We don’t feel it’s necessary to change anything.” Indeed, doctors in the Netherlands are still free to provide gender-affirming care as they see fit. The same is true of their colleagues in Finland, Sweden, France, Norway, and the U.K., where new official guidelines and recommendations are not binding. No legal prohibitions have been put in place in Europe, as they have been in more than a dozen U.S. states, where physicians risk losing their medical license or facing criminal sanctions for prescribing certain forms of gender-affirming care.

But the trend toward more conservative application of the Dutch protocol is likely to have real effects in European countries, in terms of which kids get treatment, and of what kind. Louise Frisén, an associate professor at Karolinska Institute and a pediatric psychiatrist at the child and adolescent mental-health clinic in Stockholm, Sweden, told me she worries that under her country’s new guidelines, many of her teenage patients will find it harder to access medical care. The benefits of treatment are clear, she said, and she further claimed that the policy change has caused anguish for some patients who are panicking at the looming prospect of puberty.

As for de Vries, when I spoke with her a few weeks before the article in de Volkskrant was published, she agreed that clinicians should be cautious, but not to the point where treatment becomes inaccessible. Outcomes for those with later-onset dysphoria do need to be investigated further, she acknowledged, but “if we are going to wait ’til the highest-standard medical evidence provides us the answers, we will have to stop altogether.” In that sense, Europe’s brewing disagreement over treatment could turn into paralysis. “That’s what worries me,” she said. “You will always have to work with uncertainties in this field.”

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Frieda Klotz

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April 28, 2023