Morning sickness, or hyperemesis gravidarum, is a prevalent condition affecting about seven out of ten women during pregnancy. However, until recently, the underlying reasons for its occurrence were largely unknown.

A recent study conducted by our team has identified a connection between sensitivity to a hormone abundantly produced during pregnancy, GDF15, and the risk of experiencing pregnancy sickness.

This condition can significantly impact the quality of life for pregnant women, even in cases considered mild. Severe forms, affecting 1% to 3% of women, involve intense nausea and vomiting leading to weight loss dehydration, or both, as documented in research.

In a study, it emerged as the primary cause for hospital admissions during the initial three months of pregnancy, as reported in medical literature.

Pregnancy sickness has been linked to adverse pregnancy outcomes, with its effects persisting beyond pregnancy. Some women express psychological distress and hesitation to conceive again.

The onset of symptoms early in pregnancy, resolving at the end of gestation, strongly indicates its connection to the developing pregnancy. Despite this, the precise mechanisms behind its occurrence have remained elusive, posing challenges to treatment development and contributing to the significant stigma associated with the condition.

GDF15

GDF15, a hormone known to suppress food intake in mice and linked to nausea and vomiting, is being explored as a potential therapy for obesity.

While early trials confirm its appetite-suppressing effects in humans, it also induces nausea and vomiting. GDF15 is abundantly present in the human placenta and occurs at high concentrations in the blood of healthy pregnant women.

Although it seems a plausible cause, a detailed understanding of how GDF15 influences the severity of pregnancy sickness has been lacking.

Our study employed various methods to investigate how GDF15 contributes to the risk of pregnancy sickness. Blood levels of GDF15 were measured in pregnant women admitted to the hospital for sickness and those with different reasons for admission.

While women with pregnancy sickness exhibited higher GDF15 levels, substantial overlap in GDF15 levels between groups suggested that factors beyond the absolute amount from the developing pregnancy may influence sickness risk.

Natural variations in the DNA of expectant mothers were identified as contributors to the risk of pregnancy sickness. Previous studies pinpointed DNA changes near GDF15 as significant determinants of sickness risk.

Specifically, a rare genetic mutation (present in about one in 1,500 people) impacting the composition of the GDF15 protein had a substantial effect on this risk.

To gauge the mutation’s potential impact on GDF15 levels in the bloodstream, its effects on the protein in lab-grown cells were studied. It was revealed that the mutated GDF15 molecule becomes trapped inside cells.

Furthermore, it adhered to and trapped “normal” GDF15, creating a double hit that impairs the transport of GDF15 out of cells. Healthy individuals with this mutation exhibited significantly lower GDF15 levels in their blood, aligning with these findings.

We found that prevalent DNA changes near GDF15, affecting approximately 15 to 30% of individuals, lead to reduced hormone levels. These alterations slightly elevate the risk of pregnancy sickness.

Conversely, women with the blood disorder thalassemia, characterized by consistently elevated GDF15 levels throughout life, reported significantly lower instances of nausea and vomiting during pregnancy.

A roadmap to treatment

The findings from these studies are conclusive – a predisposition to higher levels of GDF15 when not pregnant reduces the risk of pregnancy sickness. Initially, this might seem paradoxical, as how can elevated levels of a hormone that induces sickness act as a protective factor against pregnancy sickness?

In reality, several hormone systems exhibit a memory-like phenomenon, where sensitivity to a hormone is influenced by prior exposure to that hormone. This explanation appeared to be the most plausible for our results.

Supporting this theory, mice with consistently high levels of GDF15 in their bloodstream showed reduced responsiveness to an acute surge in GDF15 levels.

Our findings suggest that lower levels of GDF15 before pregnancy make women hypersensitive to the substantial amounts of GDF15 released from the developing pregnancy.

This presents two apparent approaches to treating this condition – desensitizing women to GDF15 by increasing its levels before pregnancy or blocking its action during pregnancy.

The challenge now is to develop and test strategies to achieve these goals that are safe and acceptable to women at risk from this debilitating condition.<img decoding=”async” src=”https://counter.theconversation.com/content/219663/count.gif?distributor=republish-lightbox-basic” alt=”The Conversation” width=”1″ height=”1″ referrerpolicy=”no-referrer-when-downgrade”>

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