You and I,
 Tethered forever.
 A part of you, 
 I will always be.
  
 Through you I’ve felt my first real laughter,
 Your deepest secrets perfused in me.
  
 A spec afloat in the deepest of oceans,
 Until you pulled me to the shore.
  
 Screaming for your warmth, 
 I gasped for air,
 And to you I was bound,
 Of this, I’m sure.
  
 Though the chain that bound us has decayed,
 The root of our alliance persists.
 No matter the distance,
 Far or wide,
 No greater bond exists. 

Hello everyone! Welcome back to my blog. I’ve disappeared for quite some time now, and I can list a billion excuses as to why (school, covid-19, stress, research…..etc.), but I won’t bore you with any more details. I am back again with a new and interesting science topic to share. Just to start us off, have any of you ever experienced a stomach flu? And I am not talking about the one where you feel some minor discomfort, but the kind of stomach flu where you throw-up so much, you lose a ton of weight and feel lethargic for days? Ok perfect…..well not really…but you know what I mean!

Let’s combine this idea with the morning sickness that some women experience during the earlier stages of their pregnancy. Now this looks like the perfect medley of ingredients for what we call hyperemesis gravidarum (HG). As complicated as this sounds, this is a diagnosis that a pregnant woman may receive when her pregnancy is accompanied by episodes of extreme vomiting and nausea, which can lead to further complications such as weight loss and volume depletion (blood volume contraction)(10). Women diagnosed with HG can also experience issues such as ketonuria (excretion of ketone bodies-molecules produced by the liver during period of starvation- into the urine) and ketonemia(high concentrations of ketone bodies in the blood)(3, 6). Beyond the fact that this is an extremely uncomfortable set symptoms to experience during the already taxing process of growing a fetus, this can also lead to complications in maternal and fetal health. To top off these unfortunate symptoms and complications, HG is also difficult to manage and treat.

Ok great…so now we have another item to add to our list of incurable conditions! Well, don’t lose hope just yet. Researchers around the globe are studying HG, and new questions are being answered every day. But for now, we can answer some questions about HG using the information that is already available, thanks to the experts around the world.

What is the cause of hyperemesis gravidarum?

Unfortunately, we have not yet pin-pointed the cause of HG. However, there are numerous theories that have been coined to explain the pathophysiology, and there are also a few risk factors that have been observed, which increases the likelihood of being diagnosed with HG.

What exactly are these risk factors you ask? Based on the data collected from a population-based cohort of all deliveries in Nova Scotia, Canada, hyperthyroid disorders, psychiatric illness, pre-existing diabetes, gastrointestinal disorders and asthma, are statistically significant risk factors for HG. In addition to this, singleton female pregnancies, pregnancies with multiple male fetuses, and male + female combination pregnancies, are also significantly associated with the risk of hyperemesis, compared to a singleton male pregnancy (8). There also seems to be some genetic factors contributing to hyperemesis, as it has been observed that a woman with immediate family members (ex: mother’s, sister’s etc.) who have also experienced HG, are at a higher risk for developing it themselves (10).

In addition to these risk factors, there are also theories that may explain the pathophysiology of HG. We will specifically be analyzing the hormonal contributions to HG, as well as the gastrointestinal contributions, though there are many other theories regarding this topic.

1. Hormonal theories

A widely accepted idea for the pathogenesis of HG is that it results from different metabolic and endocrine factors, some of which are placental in origin. In the first trimester of pregnancy, there is a peak in the human chorionic gonadotropin (hCG) levels, and this corresponds to the peak of HG symptoms (10, 15). In a study by Goodwin et al., it was observed that hyperemesis patients had significantly higher levels of serum hCG. Additionally, the hCG concentrations in these patients were directly correlated with their degree of vomiting (9, 12). Though this shows a promising relationship between hCG levels and hyperemesis, a causal relationship has not been established due to other studies which suggest that there is no relationship between serum hCG levels and HG (15).

Similarly, ovarian hormones such as estrogen, and progesterone have been studied in relation to HG. For one, changes in estrogen levels over the course of the pregnancy (estrogen levels rise early and decrease later in the pregnancy), seem to mirror the nausea and vomiting that are seen in both normal an HG pregnancies (10, 15). Depue and colleagues found that while hCG levels did not show a significant difference between HG patients and their matched controls, HG patients showed significantly higher free serum estrogen levels compared to the control group (7). Another reason why the ovarian hormones are suspected for contributing to HG, is because some women who take oral contraceptives (often containing doses of synthetic estrogen and progesterone), also experience nausea and vomiting. Additionally, women experiencing states of high estrogen concentration, for instance, high maternal body mass index and/or low parity (total number of pregnancies resulting in the birth of a fetus), also show a higher incidence of HG (15).

This theory implicates hormones as a contributing factor to HG and highlights the importance of the body’s ability to maintain homeostasis throughout a pregnancy. Since nausea and vomiting are normal symptoms of pregnancy in the earlier stages, it may be useful to further understand the hormonal differences between a woman who experiences these symptoms on a moderate level, against those who develop these symptoms on a severe scale. Although there has been an extensive amount research within this field, it is difficult to draw a cause and effect relationship between hormonal imbalances and the occurrence of HG, due to the ethical implications of manipulating hormone levels in a pregnant woman. Creating animal models of this condition may help us to overcome this issue and enhance our knowledge on the pathogenesis.

2. Gastrointestinal theories

Another major idea that has been linked to HG is gastrointestinal dysmotility. During pregnancy, the lower esophageal sphincter relaxes due to the increasing levels of estrogen and progesterone. This has often been associated with the heartburn that many women experience during pregnancy, but it can also lead to gastroesophageal reflux disease (GERD), which can promote the symptoms of HG, such as nausea and vomiting(10, 15).

In addition to changes in the resting pressure of the esophageal sphincter, changes in gastric rhythmic activity can also exacerbate the nausea and vomiting a woman may experience during her pregnancy. Under normal physiological conditions, there is slow wave propagations in the stomach, at a rate of 3 cycles per minute (cpm)(15). Changes in this normal, rhythmical activity has been observed to trigger different nausea syndromes (13). When Koch and colleagues measured gastric electrical activity from a group women during their first trimester of pregnancy, they observed that individuals who maintained the normal, slow wave activity, had less complaints about nausea. On the other hand, those who had lower, or higher cpm, were more likely to complain about nausea(4, 13).

Similar to the controversy surrounding the role of hCG in HG, the idea that GI dysmotility may be the underlying cause of HG is also controversial. Some studies have found no abnormalities in gastric emptying time between pregnant women with HG and non-HG pregnancies (4, 17). Some of these studies also suggest that there is no difference in gastric motility between a pregnant and non-pregnant woman (15).

Regardless of the controversies that exist in both the gastrointestinal and hormonal hypotheses, neither theories can be completely tossed aside. Maybe it’s not just a matter of one theory, instead, it may be a blend of the changes that take place in multiple systems. Maybe it’s the sum of all of the adaptations that the body undergoes during a pregnancy that leads to the severe symptoms we see in HG. So what might be the difference between a pregnant woman who develops HG, versus one that does not? There could be a multiple explanations for this. Maybe they differ in terms of genetic predispositions? Maybe one is able to maintain homeostasis more effectively than the other? Maybe psychosocial factors are involved?

A lot of these questions have been addressed by researchers, and the puzzle still remains incomplete. What this tell us then, is that HG is not just a simple process that can be attributed to one thing, or another. It is an integrative and complex diagnosis that requires a larger scale analysis. But why do we need to discover the root of the problem? And is HG really a cause for concern? How does this diagnosis impact the health of the mother and the fetus? Let’s take a look!

What are the fetal and maternal outcomes of HG?

In most cases, hyperemesis is associated with maternal weight loss, nutritional deficiencies and fluid/electrolyte imbalances, as this condition alters regular food and liquid intake (14). Studies also suggest that women with HG have a lower health-related quality of life, experience adverse birth outcomes and without intervention, may develop significant illnesses (4, 15). Some of these morbidities include acute kidney injury, liver dysfunctions and Wernicke’s encephalopathy (an acute neurological condition characterized by confusion and trouble coordinating movements) (2, 4). In addition to this, it has been observed that women who experience extreme nausea and vomiting during their pregnancy, are at a higher risk for developing high blood pressure and preeclampsia (a disorder marked by hypertension that may lead to the damage of maternal organs and poor blood perfusion to the fetus) (5). In addition to the adverse health outcomes, psychosocial outcomes, such as the mothers mental health status, and overall quality of life may also be disrupted by this condition. Research has revealed that patients suffering from severe nausea and vomiting during a pregnancy felt they had lost time from work, and lost their ability to partake in normal, everyday activities (1).

Pregnancy itself is an exhausting process and a woman undergoes a tremendous amount of physical, and mental changes that enable her to prepare to give rise to an offspring (or many). Now imagine the toll that an additional diagnosis, like HG, could have on her mental health and sense of security. Even with an abundant amount of resources that could help her manage these symptoms, this woman may continue to feel burdened and stressed by her experience. In these cases, group support and counselling may be of great benefit.

In terms of fetal outcomes, some studies have observed lower birth weight, an increase in preterm births, and fetal death to be associated with HG (4). Since this condition is marked by maternal stress, and malnutrition, this may result in poor developmental outcomes of the neonate, which can lead to long term negative consequences throughout their lifespan. In a study by Mullin and colleagues, they found that offspring from an HG pregnancy were more likely to have behavioral and psychological disorders. This included diagnoses such as depression, bipolar disorder and anxiety (16). Additionally, congenital abnormalities such as undescended testes, central nervous system malformations and hip dysplasia (partial or complete dislocation of the hip), have been observed to occur with a higher incidence rate in these offspring (16).

The negative effects of this condition on maternal and fetal outcomes emphasizes the need to rapidly diagnose and monitor women who are experiencing these complications in their pregnancy. In addition to treating the symptoms associated with HG, it is also necessary to address the psychological effects of this condition on the patients. Providing access to psychologists, educating the women and their families on the condition, and/or simply acknowledging the difficulty of managing their symptoms, may help to alleviate the additional stress that these women experience and provide them with the group support they need to carry out a successful pregnancy.

Is it possible to manage some of these symptoms? And what methods do we already have in place to support these women?

Treating HG:

Although we have not developed a single treatment to combat the symptoms of HG, there are different treatment methods that can be used to provide relief from some of the symptoms. These methods include a variety of different options, such as changes in lifestyle and diet, as well as the use of different medication.

Diet and Lifestyle:

Increasing fluid intake and modifying portion sizes to allow for the consumption of smaller meals throughout the day, are seen to be helpful in the case of mild nausea and vomiting. Additionally, modifying the diet to increase carbohydrate consumption, and decrease fat and acid consumption, also seem to benefit women who are experiencing HG. Since electrolyte imbalance is a major issue with this condition, drinks containing electrolytes and additional supplements, may be advised by a physician (11, 18).

In addition to changes in diet, women who are experiencing severe nausea and vomiting may be advised to get as much rest as possible and to avoid additional stress (18). By modifying both the diet and lifestyle under the advice of a licensed physician, a woman may experience a reduction in the complications associated with this condition.

Medication:

Antiemetic drugs may be used in the pregnancy to control the nausea and vomiting. However, some specific drugs may be contraindicated before 12-14 weeks of gestation, as they can be deleterious towards fetal development. Steroids have also been used in the treatment of HG because they have the ability to act on the vomiting centre of the brain and can be helpful in terminating vomiting (18). Although there are many studies supporting the efficacy of drugs in reducing the symptoms of HG, there may need to be additional considerations from individual-to-individual, and from case-to-case. As such, consulting a physician before taking any medication is essential.

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Regardless of what factor may be emphasized in one study or another, human physiology is intertwined and complex. Of course it is necessary to take the pieces apart to understand what role each component plays; nonetheless, it is equally critical that we put these pieces back together to appreciate how they interact as one. Maybe by doing this, we can get closer and closer to creating a targeted approach in treating HG, and support women in the wonderful journey that is pregnancy.

Quick side note: the gut microbiome seems to be a super popular topic in the research world these days. Wouldn’t it be cool to see how the gut microbiome is involved in HG? Hmmm…. I haven’t seen too many studies on this yet….let me trademark this idea real quick!

Thanks for the read. Have a great day everyone 🙂

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