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WE FINALLY KNOW THE CAUSE OF SEVERE MORNING SICKNESS. A REMEDY COULD BE NEXT.

The debilitating, sometimes fatal condition called hyperemesis gravidarum has
received scant funding and little acknowledgment, but new research may soon
yield drugs to treat it.


Around 2 percent of pregnant individuals suffer from hyperemesis gravidarum
(HG), a condition characterized by severe, persistent nausea and vomiting that
can be life-threatening.
Photograph by Joel Sartore, Nat Geo Image Collection
BySam Jones
January 11, 2024
 * 
 * 
 * 
 * 

During her first pregnancy, Marlena Fejzo experienced nausea and vomiting so
severe it landed her in the emergency room twice before giving birth. But her
second pregnancy “was so much worse. I didn’t even think it could be worse, but
it was,” recalls Fejzo, who is now a women’s health researcher at the Keck
School of Medicine of USC.

During the second pregnancy, Fejzo was given IV fluids, seven different
medications, and placed on a feeding tube. Nothing worked. At points she was so
weak that she couldn’t speak, was bedridden, and needed round-the-clock care.
Fejzo’s doctor told her he thought she was just trying to get attention from her
husband. At 15 weeks, she miscarried.

Fejzo suffered from hyperemesis gravidarum (HG), a condition experienced by
around 2 percent of pregnant individuals and characterized by severe, persistent
nausea and vomiting that can be life-threatening. Despite that, HG research is
consistently underfunded and those experiencing it are often dismissed. Fejzo’s
miscarriage was in 1999. Shortly after, she returned to her postdoctoral
researcher position at UCLA motivated to learn everything she could about HG.

Last month, Fejzo and her colleagues published breakthrough work on how the
hormone GDF15 impacts a mother’s risk of developing HG. The work could lead to
several effective treatments whose availability, some researchers say, feels
imminent. But lack of awareness and acknowledgment of the severity of HG could
stand in the way.

Morning sickness is an unpleasant pregnancy experience, but when HG—a far more
extreme condition—is lumped together with morning sickness, the women suffering
from it feel gaslit, says Kimber Wakefield MacGibbon, one of the study authors
and the co-founder and executive director of the Hyperemesis Education and
Research (HER) Foundation. HG feels like food poisoning, but with a very
important difference: vomiting does not lead to relief. “It’s a continuous
feeling that something's in your stomach that shouldn't be there,"
says MacGibbon, a registered nurse who experienced HG in both of her
pregnancies.



Dehydration and weight loss are common symptoms of HG, but the most severe cases
can lead to miscarriage and conditions in the mother such as Wernicke’s
encephalopathy, a neurological disorder caused by vitamin B1(thiamine)
deficiency that can be fatal. A number of studies have shown that babies born to
mothers with HG are at increased risk for preterm birth, low birth weight, and
neurodevelopmental disorders including speech and language delay.

“It really is a dangerous exposure in pregnancy, and it should be considered
that,” says Fejzo. “Unfortunately, it just isn’t.”


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First-line treatments for HG, including anti-vomiting and nausea medications,
are not effective for many women, says physician Jone Trovik, a professor in the
department of clinical science at the University of Bergen who was not involved
in Fejzo and MacGibbon’s study. And, even if a patient is given intravenous
fluids to help relieve dehydration and electrolyte depletion or—in the most dire
circumstances—is hooked up to a feeding tube, they may still need to terminate
their pregnancy to survive.

“As a doctor I feel very incompetent when I do not manage to help these women
avoid termination in an otherwise wanted pregnancy,” says Trovik.

Despite its severity, HG is overlooked, even by the medical community.
Obstetrics and gynecology physician and HER Foundation medical advisor Aimee
Brecht-Doscher will never forget the American College of Obstetricians and
Gynecologists annual meeting she attended alongside thousands of other
physicians in 2017, where only two presentations were given about HG, one by
Fejzo. And as Brecht-Doscher and a few other attendees sat discussing the
neglected condition, a male physician joined the conversation and announced: ‘I
know what causes hyperemesis: it's hysteria.’ “And if you believe that,” says
Brecht-Doscher, “then you don't believe that you really need to do anything to
treat people.”



Brecht-Doscher, who also was not involved in Fejzo and MacGibbon’s study,
suffered from HG in two pregnancies, one of which led to a miscarriage. “The
knee jerk reaction as a physician—especially to women who don't respond to
standard therapies—is to assume that there's a psychological component and
that's why they're not responding,” she says. “And I had learned that bias
myself as a physician prior to having hyperemesis.” Brecht-Doscher says that,
once she got HG, “I realized there was really nothing I could do to make myself
better.”


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BUILDING AN HG COMMUNITY

Following her miscarriage, one of the first things Fejzo did was create an
online survey to get a sense of HG’s prevalence and the variables that
influenced it. She was shocked by how many responses she received, including one
from MacGibbon, who Fejzo remembers writing, “after I’m done with this
pregnancy, I’m going to make a website on hyperemesis because there’s nothing
out there.”

What began as a website became the HER Foundation in 2002, a non-profit that
collaborates with universities and research studies; offers support to families;
and provides resources on HG to patients and providers—such as information on
medications and management strategies. MacGibbon says she has spoken to around
10,000 families across the globe since she launched the foundation.

Fejzo’s survey was soon posted on the HER website and, with that data, she,
MacGibbon, and colleagues showed that HG was likely heritable. Fejzo then
applied for NIH funding to study which gene(s) may be responsible but was
denied. In 2010, her brother gave her a 23andMe genetic testing kit as a
birthday gift. In addition to providing genetic information, 23andMe customers
have the option of filling out health surveys. Fejzo had an idea. “I contacted
them and asked them if they could include questions about hyperemesis, which
they did.”

In 2018, using genetic and health survey data from 23andMe participants, Fejzo,
MacGibbon, and colleagues were the first to show a link between hyperemesis and
a hormone called GDF15. GDF15 levels were already known to increase in the first
two trimesters of pregnancy and to be a driver of cachexia, a wasting syndrome
often seen in cancer patients.



Around the same time, studies showed that GDF15 binds to cells in the brain
stem, a structure responsible for basic functions like breathing and
consciousness as well as vomiting, which reinforced its likely role in HG. But
Fejzo was still perplexed as to why some people have HG in one pregnancy and not
another.


WHAT CAUSES HG?

In the recent study, Fejzo and colleagues discovered that the majority of the
GDF15 hormone comes from the baby, not the mother, and the amount produced can
change from one pregnancy to the next, depending on the genetics of the baby,
which is why mothers don’t always experience HG with all pregnancies. In
addition, a mother’s level of nausea and vomiting during pregnancy is determined
by her sensitivity to GDF15.

The researchers found that women who produce below average amounts of GDF15
before becoming pregnant are at higher risk for developing HG because they are
hypersensitive to the typical rise of the GDF15 protein in early pregnancy. By
comparison, women who produce high levels of GDF15 before becoming pregnant
report very little nausea or vomiting.

To test the hypothesis that sensitivity to GDF15 influences risk of HG,
researchers exposed mice to either a small dose of GDF15 followed by a high dose
of GDF15—comparable to levels in women with HG—or to only a single high dose of
GDF15. Mice given only one high dose began eating less and lost weight; by
contrast, the mice given a small dose of GDF15 first, and thereby desensitized,
were not impacted when given the larger dose.


PROMISING DRUGS IN THE PIPELINE 

Brecht-Doscher believes these findings will soon lead to treatments. But, she
says, there is still valid concern about giving drugs to pregnant women.
“There's a lot of history there, with other medications that were used
specifically for nausea and pregnancy that did cause harm.” One of those was
thalidomide which, in the early 1960s, was found to cause severe limb
deformities in the children of mothers who took it to relieve nausea during
pregnancy.



But Fejzo and others are optimistic because drugs that appear promising are
already being tested, albeit for other conditions. Fejzo is hoping to evaluate
drugs that increase GDF15 levels prior to pregnancy, preventing HG, as well as
drugs that decrease GDF15 during pregnancy, further staving off or mitigating
symptoms.

Fejzo is currently applying for a grant to test the diabetes drug
metformin, which increases levels of GDF15 in the blood and is already used to
increase fertility in patients with polycystic ovary syndrome (PCOS) and in some
cases of gestational diabetes. There are also GDF15 blocking drugs in clinical
trials for cancer patients with cachexia. Fejzo hopes that, once those drugs are
shown to be safe in those trials as well as in pregnant animal models, they can
be tested in pregnant women as well. On January 9, San Francisco biotech company
NGM Bio announced that they are talking with the FDA about beginning clinical
trials in HG patients with their GDF15-blocking drug, NGM120. Fejzo will serve
as an advisor to NGM Bio in the process.




RELATED TOPICS

 * WOMEN
 * HEALTH
 * SEXUAL HEALTH
 * MEDICINE
 * PSYCHOLOGY
 * MENTAL HEALTH
 * DRUGS


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