Dr. Fejzo and MacGibbon’s historical timeline that sets the stage for testing novel treatments for Nausea and Vomiting during Pregnancy (NVP) and Hyperemesis Gravidarum (HG).
1988 – Brown University
While an applied math major, Marlena Schoenberg (Fejzo) took Dr. Hagy’s human genetics course and realized she wanted to be a geneticist.
1990-95 – Harvard University
Fejzo works under the mentorship of Dr. Cynthia Morton for her PhD on the understudied women’s health condition, uterine fibroids.
1995 – Plenary Speaker
Fejzo speaks on the identification of the 1st genes for uterine fibroid tumors at the American Society for Human Genetics.
1996 – University of California, San Francisco
During postdoctoral studies of breast cancer, Fejzo is treated for hyperemesis gravidarum, but is never diagnosed.
1997 – Fejzo gives birth to her first child, the same year, GDF15 is discovered by 3 separate groups.
1999 – University of California, Los Angeles
During postdoctoral studies of the genetics of multiple sclerosis, Fejzo is diagnosed with and loses a baby in the 2nd trimester with hyperemesis gravidarum (HG).
MacGibbon gives birth to her first child after hyperemesis gravidarum persisting through delivery.
2000 – First HG Survey
Though unsupported by the UCLA Genetics Department Chair, Fejzo decides to dedicate her life to HG research. She initiates her first HG study by posting a survey on the internet with help from her brother, Dr. Rick Schoenberg, a statistician at UCLA. Responses are faxed to her, providing some answers. Kimber MacGibbon answers Fejzo’s survey and reveals she is creating an HG website.
2000 – MacGibbon-Fejzo Partnership, Ovarian cancer research
MacGibbon births the HER Foundation website, www.hyperemesis.org, the leading voice for HG.
Fejzo starts a faculty position studying ovarian cancer with Dr. Dennis Slamon.
2001 – Completing her family, Familial Aggregation
Fejzo’s twin daughters are born through the selfless help of a surrogate mother, further inspiring Fejzo to give back.
Fejzo’s survey data reveals evidence of familial aggregation, supporting a genetic etiology, and is presented at the American Society of Human Genetics.
2003 – Survey 2.0
Fejzo and MacGibbon revamp the survey and host it on the HER Foundation website to further progress on HG.
2005 – Fejzo joins USC, Congressional Briefing
Fejzo presented the HG survey results to USC Maternal/Fetal Medicine Chair T. Murphy
Goodwin and she was offered a voluntary faculty appointment at USC to work on HG. Then HER Foundation founders MacGibbon and the Kings meet in person with Fejzo and
Goodwin at USC to strategize on HG research and advocacy.
Fejzo, MacGibbon, Goodwin, and others were present at the Congressional Briefing on HG, which was led by now-HHS Secretary Xavier Becerra.
2007 – Genetics & Epidemiology Study of HG
Fejzo officially partners with HER Foundation and USC and begins enrolling patients, collecting saliva samples for DNA, and survey data on HG cases and unaffected acquaintances.
2009 – Extreme weight loss & behavioral disorders
Fejzo, MacGibbon, and the team published that 26% of survey participants lose more than 15% of pre-pregnancy weight—the first reporting of PTSD in mothers and >9% of children with behavioral disorders.
“Symptoms and Pregnancy Outcomes Associated with Extreme Weight Loss among Women with Hyperemesis Gravidarum” (Journal of Women’s Health, 2009).
While enrolling participants and collecting and analyzing survey data, Fejzo continues her work on ovarian cancer at UCLA.
2010 – 23andMe, Inc.
Fejzo receives a 23andMe kit for her birthday. She contacts 23andMe to add survey questions on HG.
2011 – Getting Answers
Fejzo, MacGibbon and team publish:
“Familial aggregation of hyperemesis gravidarum” (AJOG, 2010).
“Posttraumatic stress symptoms following pregnancy complicated by hyperemesis gravidarum” (Journal of Maternal-Fetal and Neonatal Medicine, 2011).
“Recurrence Risk of Hyperemesis Gravidarum” (J Midwifery Womens Health, 2011).
“Prenatal exposure to hyperemesis gravidarum linked to increased risk of psychological and behavioral disorders in adulthood” (Journal of Developmental Disorders of Health and Disease, 2011).
2012 – Getting Answers
Fejzo, MacGibbon, and team publish:
“No Increased Risk of Psychological/Behavioral Disorders in Siblings of Women with Hyperemesis Gravidarum (HG) unless their Mother had HG” (Reproductive Toxicology, 2019).
Paternity change does not affect HG recurrence risk suggesting mother’s genes play a major role.
2013 – Getting Answers
Fejzo, MacGibbon and team publish:
HG associated with 4-fold increased risk of adverse outcomes including preterm birth.
“Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum” (European Journal of Obstetrics & Gynecology and Reproductive Biology, 2013).
2015 – Getting Answers
Fejzo, MacGibbon, and team publish:
First publication of significantly increased risk for neurodevelopmental delay in children.
“Neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum” (European Journal of Obstetrics & Gynecology and Reproductive Biology, 2015).
Psychiatric factors do not increase risk.
NIH grant rejected, criticizing 23andMe and crowdsourcing as a weakness, not a strength.
1st World Colloquium on HG, Bergen, Norway.
2016 – 23andMe! Ondansetron
Fejzo receives 23andMe data linking GDF15 and IGFBP7 to HG, replicates the findings in her cohort, and writes and submits the manuscript.
Fejzo, MacGibbon, and team published 1st paper on >1000 ondansetron exposures and fetal outcomes in the US.
“Ondansetron in pregnancy and risk of adverse fetal outcomes in the United States” (Reproductive Toxicology, 2016).
Fejzo, MacGibbon, Chan, and team won 2nd place in the Code for the Mission contest, securing UCLA funding for the first HG Care App which is currently being rebuilt on a multi-platform technology.
2017 – ICHG, Windsor
May 2017 ACOG, San Diego, Fejzo makes the first presentation linking GDF15 to HG and suggests a therapeutic strategy based on her findings.
After learning about GDF15 at a Novo Nordisk board meeting, Cambridge endocrinologist Stephen O’Rahilly hypothesizes GDF15 may be involved in HG etiology.
Oct 2017 ICHG, Windsor, Fejzo presents her data showing both genetic variants and circulating levels of GDF15 and IGFBP7 are significantly associated with HG. ICHG 2017 presentation
Stephen O’Rahilly attends ICHG. Fejzo shows him her results linking both the GDF15 gene and GDF15 blood levels to HG.
Following this meeting, O’Rahilly’s team assays GDF15 in blood from pregnant patients taking antiemetics and/or with prolonged symptoms, and quickly posts results on Biorxiv, ahead of Fejzo’s publications.
Fejzo’s 2nd NIH grant to sequence her cohort is rejected.
2018 – It’s out-GDF15 and HG!
Fejzo and team publish:
“Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum” in Nature Communications.
“Evidence GDF15 Plays a Role in Familial and Recurrent Hyperemesis Gravidarum”.
Fejzo, MacGibbon, and team publish:
“Analysis of neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum reveals increased reporting of autism spectrum disorder” (Reproductive Toxicology, 2019). Pre-Print, 2018.
2018-2019 – Regeneron
In 2018 Ann-Hwee Lee, a scientist at Regeneron reached out to Fejzo to discuss her Nature Communications paper and offered to collaborate. Fejzo asks for help with sequencing her cohort of 926 HG cases and 660 unaffected controls she began collecting in 2007. Regeneron agrees!
Fejzo and team publish first study linking altered serum levels of GDF15 and IGFBP7 to HG.
“Analysis of GDF15 and IGFBP7 in Hyperemesis Gravidarum Support Causality” (Geburtsh Frauenheilk, 2019).
Fejzo presents her study validating the association between HG and the receptor for GDF15, GFRAL, further implicating the pathway in HG etiology. She confirms the progesterone receptor is associated with HG.
SMFM 2019 – Presented poster on “Hormone receptor genes PGR and GFRAL linked to Hyperemesis Gravidarum” and Published “Hormone receptor genes PGR and GFRAL linked to hyperemesis gravidarum” (AJOG, 2019).
2020 – Pandemic Progress
SMFM, Fejzo presents validation of a second HG-associated GDF15 variant, further implicating GDF15.
Despite the pandemic, Regeneron gets the sequencing results to Fejzo on schedule and she and Ben Busby (DNA Nexus) begin analyzing the data.
After years of generously allowing Fejzo to work part-time on cancer, Slamon gives Fejzo an ultimatum, cancer or HG. Fejzo picks HG and leaves UCLA after 20 years.
Tim Opler invites Fejzo to be CSO of Materna Biosciences, to develop HG treatment based on her findings.
2021 – HELP Score
MacGibbon, Fejzo and team publish validation of a scoring tool to screen HG patients.
“HyperEmesis Level Prediction (HELP Score) Identifies Patients with Indicators of Severe Disease: a Validation Study” (Geburtsh Frauenheilk, 2021).
Fejzo presents sequencing results at ASHG that show GDF15 is the only significant risk gene in her cohort and presents the first mutation identified in GDF15.
2022 – It’s out – GDF15 again!
Fejzo and her team published the first coding variants associated with HG, which are both in GDF15. One mutation in GDF15 increases HG risk>10-fold, and another is the only exome-wide significant variant in her cohort, providing strong causal evidence for GDF15.
“Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum” (BJOG, 2022).
Fejzo, MacGibbon, and team published survey results showing 14% of people with HG treat with cannabis primarily because current antiemetics are ineffective.
“Patterns of Use and Self-reported Effectiveness of Cannabis for Hyperemesis Gravidarum” (Geburtshilfe Frauenheilkd, 2022).
ACOG 2022 – Poster on “Genetic predictors of ondansetron effectiveness and recurrence risk for hyperemesis gravidarum”
Feb. 2022 – Paradox
O’Rahilly shares preprint of GDF15 assay problem with Fejzo and Fejzo asks him why participants with DD genotype have higher GDF15 than HH by Roche assay. O’Rahilly says patient characteristics weren’t matched.
Fejzo sequences children of moms with mutation and discovers mothers who do NOT pass on mutation still get HG.
O’Rahilly tells Fejzo the majority of GDF15 in pregnancy comes from the fetus (Richard Kay’s data).
Fejzo, O’Rahilly, and Marko Hyvonen discuss possible theories to explain the paradox, and discuss working together.
Fejzo shares mutation discovery with O’Rahilly prior to publication.
Fejzo discusses the idea of desensitization prior to pregnancy with O’Rahilly.
March 2022 – Competition!
Nuno Rocha shows mutant GDF15 is not secreted.
O’Rahilly contacts Steve Charnock-Jones and Gordon Smith to rush their collaboration to publish before Fejzo.
April 2022 – Collaboration
O’Rahilly changes strategy and reaches out to Fejzo and asks her to hold off on publication and they make a deal to publish together, he as last and corresponding author and she as 1st author.
October 2022 – ICHG, London 2022
Fejzo and O’Rahilly meet to discuss the manuscript they plan to submit to Nature.
Fejzo presents the work leading up to the paradox at ICHG, but the solution-that people with HG have lower levels of GDF15 prior to pregnancy and are thus hypersensitive to its rise in pregnancy, is under wraps pending O’Rahilly’s patent.
2023 – It’s out – GDF15 mechanism!
Fejzo’s science profile by Alice Callahan makes the front page of the New York Times.
Fejzo was invited to speak at FORTUNE’s Most Powerful Women Next Gen.
Fejzo begins consulting for NGM Bio, a company with a GFRAL inhibitor.
Fejzo joins the Center for Genetic Epidemiology, USC.
Fejzo is honored Fiercest Women in Life Science, 2023.
Nature paper revealing the mechanism behind GDF15’s role in morning sickness and Hyperemesis Gravidarum is published. The findings suggest a way not only to treat, but also to prevent HG.
2024 – Harmonia Healthcare
NGM Bio announces working with FDA to find a path forward in testing NGM120 in HG patients, with Fejzo as their consultant.
Fejzo signs on as CSO of Harmonia Healthcare to help develop testing for HG and build infrastructure for research, clinical trials, and improved care. MacGibbon partners on behalf of the HER Foundation as an advocate for the HG community.
Fejzo is honored Time Women of the Year for discovering the gene behind morning sickness and HG.
