Ending Morning Sickness - Little, Big Science : Little, Big Science

Morning sickness, i.e., nausea and vomiting during pregnancy, is an unpleasant but very common phenomenon. In a small proportion of women, the condition is so severe that it can endanger both the pregnant woman and the fetus. In recent years, researchers have discovered a link between the condition and a hormone secreted by the placenta early in pregnancy. A new study shows how the ratio between hormone levels originating from the fetus and the mother’s levels of the same hormone before pregnancy may predict the severity of morning sickness. The discovery could offer new ways to treat, and perhaps even prevent, its most severe form—hyperemesis gravidarum.

When you write your next Hollywood film script, what will be the moment when your audience suspects that the female protagonist is pregnant? Probably when she appears in pajamas, gazes at her reflection in the toilet water, and then pukes her guts out. Nausea and vomiting, aka "morning sickness", during pregnancy are unpleasant but very common phenomena: more than two-thirds of pregnant women experience them to some extent during the first trimester. In 0.3%–3% of women, the condition is particularly severe—they suffer from a syndrome called hyperemesis gravidarum, excessive vomiting during pregnancy, sometimes throughout the entire pregnancy. The syndrome greatly impairs the quality of life of the women who experience it, may cause dehydration requiring hospitalization, and can endanger the fetus [1].

In 1999, Dr. Marlena Fejzo lost a pregnancy due to a complication of hyperemesis gravidarum, and has since devoted her scientific career to finding the cause of the syndrome [2]. Initially, Fejzo and her colleagues searched for genetic differences between women who had suffered from excessive vomiting during pregnancy and women who were not prone to pregnancy-related nausea. They identified a region of the genome containing differences in DNA sequence associated with an increased risk of the syndrome. When they examined this region in depth, they discovered that it contains the gene that produces a growth factor called GDF15, which, among other roles, is important for fetal development [3,4]. During pregnancy, large amounts of the hormone are secreted from the placenta into the mother’s bloodstream, and then to her cerebrospinal fluid. There is a positive correlation between the hormone’s levels in a pregnant woman’s blood and the incidence of nausea in the first trimester, and women with hyperemesis gravidarum have particularly high levels of it [5]. When GDF15 reaches the brainstem through the cerebrospinal fluid, it suppresses appetite and causes nausea [6].

In a new study led by Fejzo [7], she and her colleagues managed to decipher precisely how GDF15 affects the severity of pregnancy-related nausea, and also propose a strategy for treating it. As noted above, certain variants of the gene that controls GDF15 production in the mother increase her risk of hyperemesis gravidarum. Yet it is GDF15 originating from the fetal genome and released by the placenta whose levels rise in the blood. This finding led the researchers to hypothesize that interactions between the levels of hormone originating in the mother and those originating in the fetus may ultimately determine the severity of morning sickness.

Next, the researchers measured GDF15 levels in non-pregnant women to determine its baseline blood levels. They found that women who had previously suffered from excessive vomiting during pregnancy had lower GDF15 levels than women who were not prone to the syndrome. The researchers showed that the genetics of women who suffer from the syndrome probably mainly affects the hormone’s baseline levels in their blood, so that under normal conditions it is produced in relatively low amounts. In other words, the jump from low baseline levels to the high levels produced by the fetus is likely what determines the severity of nausea. This gave rise to a new hypothesis: when pre-pregnancy levels of the hormone are relatively high, the brainstem develops some tolerance to it and therefore responds less strongly to the hormone from the fetus.

To test the hypothesis that the development of tolerance determines symptom severity, the researchers designed a two-stage experiment. In the first stage, they injected one group of mice—consisting of both males and non-pregnant females—with a preliminary treatment of human GDF15. The hormone was administered at a low dose that remained in the bloodstream for several days. Another group received a placebo treatment. In the second stage, the mice were given a high dose of GDF15, and their eating patterns were examined. The researchers expected to find a reduction in the amount of food the mice ate because, as noted, GDF15 causes nausea in humans while also suppressing appetite. The experimental results showed that the preliminary treatment, which mimics women’s baseline hormone levels before pregnancy, prevented the loss of appetite caused by the high dose of GDF15. This high dose mimics the large amount secreted by the fetus at the beginning of pregnancy in humans. The mouse experiment indicates that deliberately inducing tolerance may moderate the effect of a spike in GDF15 levels in mice, and could perhaps lead to the development of a similar treatment for women who experience the same spike early in pregnancy.

In summary, the new study identifies the factor that determines whether a woman will experience morning sickness in general, and hyperemesis gravidarum in particular: tolerance to fetal GDF15, which develops as a result of the woman’s pre-pregnancy baseline GDF15 levels, or the absence of such tolerance. This suggests a potential new strategy for predicting hyperemesis gravidarum and preventing it in the future. For example, it may be possible to develop a screening test for GDF15 that would help assess the risk that a woman planning a pregnancy will experience severe nausea. If she is found to be at high risk, she might be given artificial GDF15 treatment before becoming pregnant to promote the development of tolerance—provided, of course, that such treatment is proven safe for both mother and fetus. This study is another small step toward understanding a phenomenon that has an enormous impact on the lives of many women, including Dr. Fejzo herself.

Hebrew editing: Galia Halevy Sadeh

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By:

Elee Shimshoni, PhD

Elee serves as Scientific Director at “Little, Big Science.” She holds a PhD in Biology from the Weizmann Institute and completed her postdoctoral training at Harvard and MIT. Her expertise lies in cancer, inflammation and metabolism, as well as in developing complex human-cell based model systems of disease.

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