Have We Figured Out What Causes Nausea During Pregnancy? The GFD15 Hormone Might Be The Answer

Nausea and vomiting in pregnancy are common, especially during the first trimester. The prevalence rates are fifty to ninety percent during the first three months of pregnancy. Commonly called “morning sickness”, this condition can cause significant quality of life disruption for the mother.

Severe cases (hyperemesis gravidarum) can require hospitalization and acute care to prevent weight loss and imbalance of electrolytes. In recent studies, a hormone has been isolated that may affect the onset and severity of nausea and vomiting in pregnancy. Previously, the causes and contributing factors of this condition were not well understood. 

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What is The Hormone Linked to Morning Sickness?

The hormone implicated by a growing body of scientific evidence is growth differentiation factor 15 (GDF15). High levels of this hormone in the blood of the mother appear to increase the incidence of nausea and vomiting in pregnancy. This hormone signals somatic distress in the brain and may serve to protect the woman and fetus from food-borne illnesses. In women with hyperemesis gravidarum (HG), levels of GDF15 were high compared to those who did not experience nausea and vomiting. Confounding factors such as body mass index, age, and pregnancy timeline were accounted for in the research.

How Does This Hormone Affect Pregnant Women?

GDF15 is produced by the fetus and acts on the brainstem. Its production plays a role in maintaining early pregnancy and promoting placental formation, but very high levels of the hormone may have adverse effects. GDF15 is produced in times of stress, possibly as a protective mechanism for the mother and fetus. Its production may serve to protect the mother from food poisoning and potential toxins, especially in early pregnancy when the fetus is especially vulnerable.

This biological mechanism would have been especially important before modern refrigeration when the mother could have more frequent exposure to harmful bacteria and parasites. Varying sensitivity levels of the mother to GDF15 appear to affect nausea and appetite in pregnancy. There also seems to be a genetic link between sensitivity to the hormone and propensity for developing NVP. Additionally, Fejzo and other researchers isolated a specific mutation called C211G in GDF15 that can predispose women to severe HG. 

Could This Lead to a Morning Sickness Cure?

Better treatments, or even a cure for morning sickness, would be revolutionary in obstetric medicine and would improve the lives of women worldwide. The recent information discovered about GDF15 shows promise for improved outcomes for women with NVP. Current thought is that sensitizing a woman to GDF15 before pregnancy may blunt her response to the hormone when it is produced in large amounts by the fetus.

In mice studies, when a large bolus of GDF15 is introduced, appetite reduces and weight loss occurs. However, when mice in the study were pretreated with GDF15 before large amounts were infused, they had a “blunted acute response” to the hormone.

In theory, women sensitized to GDF15 before becoming pregnant may have a lessened response to the hormone when levels rise after pregnancy occurs. This desensitization theory may change the current treatment course for NVP and HG. Using this logic, women with chronically high levels of GDF15 from other diseases should experience less nausea and vomiting during pregnancy.

This theory was tested, women with thalassemia have chronically high levels of GDF15 and there was a “strikingly lower prevalence of symptoms of NPV in the women with thalassemia: only approximately 5% of women with thalassemia reported any nausea or vomiting compared to greater than 60% of the controls”.

Additionally, it stands to reason that “blocking GDF15 action in the pregnant mother should be a highly effective therapy for women suffering from HG”. Metformin, a medication used primarily for diabetes greatly increases the levels of GDF15 in the body.

Using metformin before pregnancy to desensitize the woman to GDF15 before nausea can occur is a possible treatment. However, this potential prophylactic treatment requires a careful analysis of safety if used during pregnancy. Additionally, metformin can cause side effects, including gastrointestinal distress. The side effect profile of this medication should be taken into account before it is utilized as a preventative therapy for NVP. 

What Treatments Are Available For Women Who Experience Morning Sickness?

Several interventions are available for women experiencing nausea and vomiting during pregnancy. These range from lifestyle interventions to acute treatment for HG. If nausea is the primary symptom, patients are advised to avoid an empty or very full stomach. Because nausea may be worse in the morning, a balanced snack upon waking may be preventative.

Balanced snacks and meals with fat, protein, and carbohydrates can prevent nausea, and it is not advised to skip meals. Avoiding a very full stomach may involve splitting up meals into smaller increments every few hours. Avoiding foods with strong odors, spices, and acidity may help relieve symptoms. Fluids should be encouraged in whatever form is tolerated, including popsicles. 

The initial medication treatment for NVP is pyridoxine (vitamin B6), a medication with minimal adverse effects. This medication reduces nausea but does not always reduce vomiting frequency. If pyridoxine does not relieve symptoms, a combination of doxylamine-pyridoxine may be used and has been shown to provide modest relief of nausea and vomiting. Doxylamine is an antihistamine that is safe during pregnancy.

If these are ineffective, an additional antihistamine can be integrated such as diphenhydramine. Meclizine and scopolamine are also antihistamine treatment options traditionally used to treat motion sickness. The next step is typically adding a dopamine receptor antagonist. Examples include metoclopramide (Reglan) and promethazine (Phenergan). These medications can be used in pregnancy with a careful risk versus benefit analysis. The risk of overall fetal risk is low with dopamine receptor antagonists. Because the efficacy of these medications is variable, additional treatments and prevention for nausea and vomiting in pregnancy are necessary. 

How Long Does Morning Sickness Last?

Nausea and vomiting during pregnancy often occur in the first three months of gestation. Most symptoms occur in the morning but many women have nausea throughout the day. Symptoms of NVP resolve around 14 weeks for most women. Some women have symptoms in the second trimester and a small population experiences nausea and vomiting throughout their pregnancy.

The symptoms may peak around eight to ten weeks of pregnancy, though this timing varies. It is theorized that the nutritional needs of the growing fetus (adequate calories) outweigh the risk of food-borne illnesses in the second trimester, so the mechanism of nausea and vomiting is reduced.

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Key Takeaways

Nausea and vomiting in pregnancy can cause symptoms ranging from mild to debilitating, and additional preventative measures and treatments would improve the quality of life for many pregnant women. Preventing hyperemesis gravidum could help women avoid hospitalization and potentially dangerous levels of dehydration and electrical imbalances.

Some information about GDF15 was established before recent studies, but this information was limited. The recent studies correlating levels of the hormone with the severity of NVP show promise in preventing this condition. These results show a possible causal link between GDF15 and nausea and vomiting during pregnancy. 

More clinical trials are necessary to establish the safety of GDF15 sensitization therapy in human subjects, but initial animal studies are promising. Medication therapies could be produced that block the effects of GDF15 and prevent high levels in the circulating maternal blood. Established therapies such as metformin that raise levels of GDF15 could be used as prophylactic therapy, if safety is established and side effect profiles are favorable for patients.

In other treatment therapies, antibodies are used to reduce the diffusion of certain molecules through the placenta. It is possible that antibodies could be utilized to provide a “safe blockade of GDF15 signaling”. Though additional studies are necessary, these findings related to GDF15 and nausea and vomiting during pregnancy may pave the way for preventing and treating this condition.