HER’s Dr. Fejzo presented at India’s AICC RCOG North Zone Annual Conference 2022. The virtual conference had 1200+ registrations and Dr. Fejzo’s session was viewed by over 400 delegates. The presentation was divided into 3 parts covering the latest Hyperemesis Gravidarum (HG) research showing 1) the nausea and vomiting hormone GDF15 is the most likely cause of HG, 2) there are adverse maternal and child outcomes associated with HG including increased risk for maternal suicidal ideation and child neurodevelopmental disorders/delays, and finally, 3) reviewing information and tools available at HER Foundation to help with implementing earlier screening and more frequent follow-up of HG patients.
Hyperemesis Gravidarum: Causes, Consequences, Care
Hyperemesis gravidarum maps at the end of the clinical spectrum and is generally diagnosed when other causes of nausea and vomiting of pregnancy (NVP) are excluded. Symptoms begin early in pregnancy, affect daily activity, and there is an inability to eat/drink normally. Patients generally have signs of dehydration and weight loss greater than 5% of pre-pregnancy weight. HG is often associated with electrolyte imbalance and can require medication, intravenous fluids and/or supplemental nutrition, hospitalization, and support.
A genetic approach to find the cause was applied because decades of research using other methods have failed. HG is highly heritable based on twin studies, and there is a 17-fold increased risk of having HG if your sister had it. Importantly, genome-wide and exome-wide association study approaches to etiology are unbiased with respect to genes involved-all genes are scanned including genes coding for hCG, historically hypothesized to be the cause.
In partnership with the personal genetics company 23andme, over 15 million variants were compared between DNA from >1300 people with HG and >15,000 people with no NVP. GFD15 was the greatest genetic risk factor (p= 10-15). A second scan of over 50,000 participants included ends of the NVP spectrum, but also included people with slight, moderate, and severe nausea in pregnancy. In that scan, again GDF15 was the greatest genetic risk factor (p=10-41). Additional genes were also associated, including a gene coding for the brainstem restricted receptor for GDF15, GFRAL.
When performing a conditional analysis, another GDF15 variant inherited separately was also identified. Thus, two variants in GDF15 inherited from two separate ancestors are associated with HG, as well as a variant in the receptor for GDF15. This strongly implicates the pathway plays a role in the etiology.
To replicate findings in a separate population using a separate genetic technique, a whole-exome sequencing study was performed comparing 926 cases to 660 controls, and the only common variant significantly different, was again a variant in GDF15. This study contained people of different ancestries, and the same variant in GDF15 showed a trend towards association in populations of minority ancestries as well, suggesting it may be generalizable, but larger studies are needed.
In addition to the common variant associated with HG in GDF15 by whole-exome sequencing, we also identified a rare mutation in GDF15, which was the only variant occurring in >10 cases and no controls. While these studies have identified multiple variants associated with GDF15, none were identified for hCG. Therefore, it is unlikely hCG is a causal hormone, while genetic evidence strongly supports GDF15 plays a role.
In addition to geneticts, evidence supporting a role for GDF15 includes the fact that among healthy tissues, GDF15 expression is highest in the placenta, and increases significantly in the first trimester. Lower serum levels and/or GDF15 variants are associated with lower NVP symptoms and carrying a male fetus. Conversely, higher serum levels and/or GDF15 variants are associated with antiemetic use, second trimester vomiting, and hospitalization. GDF15 causes appetite/weight loss, taste aversion, and emesis in nonpregnant animal models. In addition to placental production of GDF15, it is a cellular stress hormone that is upregulated in other tissues in response to nutrient deficiencies, long-term fasting, hyperthyroidism, and infection, all conditions associated with HG pregnancies. This may explain why a genetic predisposition to abnormal GDF15/GFRAL/RET signaling can evolve from NVP to HG.
Fascinatingly, GDF15 causes cancer cachexia, a condition with similar symptoms to HG- loss of appetite, weight loss, and muscle wasting. HG patients may have more than twice the GDF15 increase compared to cachexia patients, and the rapid increase in GDF15 may be what causes HG patients to feel like they are dying. HG patients should be taken seriously and treated with care and compassion, just like cachexia patients.
These studies may have significant clinical implications in the future. In nonhuman primates, GDF15 inhibition increases food intake in monkeys treated with the highly emetogenic drug cisplatin. In addition, blocking GDF15 decreases vomiting bouts in monkeys treated compared to those not treated with a GDF15 inhibitor. Drugs targeting GDF15/GFRAL show great promise in animal models and are now in cancer clinical trials. Work is also ongoing to understand how risk genes can be used to predict HG.
This is important because new evidence reveals maternal and child morbidity/mortality associated with HG, including a high risk of suicidal ideation and post-traumatic stress disorder. Many patients lose over 15% of their pre-pregnancy weight and have symptoms lasting until term. Patients report detached retinas, pneumothorax, esophageal tears, and rib fractures from violent vomiting, and can have liver, kidney, and gallbladder dysfunction from prolonged malnutrition. HG is the 4th most common cause of death in pregnancy in Botswana. Maternal deaths in the US and UK have also recently occurred. Most deaths were caused by severe nutritional deficiencies-mainly vitamin B1/thiamin deficiency which can lead to Wernicke’s encephalopathy, brain damage characterized by ataxia, ocular, and mental status changes. Patients can also suffer from severe electrolyte imbalances that can lead to hypokalemia, prolonged QT intervals, and cardiac arrest. Thromboembolism and thyrotoxicosis have also caused deaths secondary to HG.
New evidence also identifies negative offspring outcomes. There is a 5-fold increased risk of having a baby born small for gestational age (SGA) and an increased risk of preterm birth. Importantly, a recent study showed SGA risk is higher for HG than for recreational drug use, smoking, chronic hypertension, pre-gestational diabetes, and preeclampsia. These other exposures/conditions and associated risks are taken seriously, yet HG and its risks are often trivialized. HG is associated with lower birthweight, smaller head circumference, and decreased brain size. Several studies now provide a consensus that HG is a teratogen affecting brain development, with increased risk of neurodevelopmental delay, autism spectrum disorder, and for patients not supplemented with folic acid, neural tube defects. In addition, there are cases of vitamin K deficient dysmorphology. Adverse outcomes directly linked to vitamin deficiencies prove that in the case of HG, the fetus is not always getting everything it needs.
The genetic findings may lead to better prediction, diagnosis tools and treatments, but for now the adverse maternal and child outcomes suggest that at a minimum, clinicians must be more proactive. This includes earlier screening for HG. Patients may have symptoms prior to their first office visit. Therefore, at a minimum, earlier screening should occur for patients with increased risk for HG. In addition, there should be frequent follow up to monitor symptoms and confirm the patient is not deteriorating.
Factors associated with increased risk for HG include having a previous HG pregnancy and/or a family history of HG. Other factors associated with risk include asthma, allergies, infections, carrying multiples, carrying a female fetus, younger age, diabetes, African or Asian ancestry, hyperthyroid disorders, and carrying risk genes.
A free Application for patients with iPhones can improve quantifying HG, patient-provider communication, and care. The HG Care App allows the patient to enter symptoms, monitor medications, and summarizes data in a report sharable with providers. Thus, providers can monitor patient progress and determine whether the patient needs a change in medication/care. Alerts let patients know to contact their doctor, for example, if they are dehydrated or malnourished.
It is important to follow-up with the patient at least weekly. The HELP Score is a short survey that identifies areas requiring attention. Patients can fill it out in the waiting room, at home, or in the HG Care App. Answers falling in the last two columns alert the doctor towards problems areas-for example, if medications are not staying down.
Medication safety is a risk benefit assessment. For example, HG patients that did not take ondansetron had a higher therapeutic termination rate and 1st trimester miscarriage rate than HG patients taking ondansetron. Subsequently, patients who used ondansetron had a higher term birth rate at term (79.9% vs 52.5%), comparable to patients that did not have HG (78.2%). Meanwhile, the rates of birth defects are very similar for both the ondansetron/HG group and NO ondansetron/HG group. Thus, it may be that HG is associated with increased risk of birth defects, independent of medication prescribed.
Frequent follow-up is recommended because medications do not always work. Ondansetron was reported to be the most effective antiemetic with 80% of patients reporting symptom relief. However, when patients were asked whether they gained weight within two weeks of starting treatment, approximately 75% of patients reported not gaining weight within two weeks of starting any prescribed medications. Thus, patients may not be getting enough nutrients, even if they say medications are helping. Nutrition should be monitored, especially in the second and third trimester where inadequate maternal weight gain is associated with increased risk for adverse outcome.
Another reason for frequent check-ins is that HG is associated with termination and suicidal ideation. A recent study revealed over half of HG patients consider termination and over a quarter consider suicide. Patients who terminate are 3-times more likely to state their healthcare providers were uncaring or did not understand how sick they were.
Thus, herein I leave you with three important conclusions. Firstly, the cause of HG is most likely altered signaling of the nausea and vomiting hormone GDF15. Although other factors may be involved as well, mounting evidence suggests this is the most likely factor involved in causing HG. Secondly, there are significant adverse maternal and child outcomes associated with HG. Long-term outcomes include posttraumatic stress following an HG pregnancy, as well as neurodevelopmental delay in children. And finally, to limit these adverse outcomes, providers must implement earlier screening, treatment, and support, with frequent follow-up, to ensure pregnant patients are getting the nutrition and care they need.
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