Empowering Fertility - Hyperemesis: An Overview 
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Hyperemesis: An Overview 

By Paul Bergh, MD

At a Glance:

  • Hyperemesis Gravidarum (HG) is serious, debilitation condition with potentially severe consequences for both mother and baby.
  • It occurs between 4-6wks and 16-20wks of pregnancy and affects 1.2% of pregnant women
  • HG is the most common reason for hospitalization in the first half of pregnancy and is only second to preterm labor as a reason for hospitalization in pregnancy.
  • Two thirds of patients with HG have a physiological stimulation of the thyroid gland that leads to hyperthyroidism – referred to as gestational transient thyrotoxicosis (GTT)
  • Risk factors include:
    • High hCG (multiple pregnancy, gestational trophoblastic disease)
    • Infection with Helicobacter pylori
    • History of HG with previous pregnancy or of HG in mother or sister
    • Young age, first pregnancy, fetal triploidy, fetal trisomy, hydrops fetalis
  • Maternal Consequences:
    • Greater than 60% of patients with HG will develop suboptimal stores of essential vitamins.
    • Weight loss, malnutrition and electrolyte deficiency that can lead to severe neurologic symptoms and death
    • Repeated vomiting can lead to injury of the esophageal-gastric mucosa
    • HG imposes an increased economic burden due to the need for more medical care and resultant missed work
    • Increased stress and risk of anxiety and depression as well as post-traumatic stress syndrome
  • Fetal Consequences
    • Increased risk of preeclampsia, placental abruption, and small-for-gestational-age birth babies
    • Increased risk of depression, bipolar disorder, and anxiety in adulthood.
    • Reduced insulin sensitivity as adults.

Introduction

Nausea and vomiting in pregnancy are so common that the combination  has a name, “morning sickness” and it is considered a normal part of pregnancy.  Symptoms usually begin between at 4-6 weeks of pregnancy and peaks at 12 weeks.  For most women, the symptoms gradually abate between 16wks and 20 weeks of pregnancy except for an unfortunate 10% who will experience “morning sickness” throughout their entire pregnancy.   In the United States, 70%  of pregnant women suffer from morning sickness but approximately 1.2% of pregnant women will go on to experience a more severe form called hyperemesis gravidarum (HG).   While there is no universal definition, HG is characterized by severe and protracted nausea and vomiting, which can lead to dehydration, electrolyte imbalance, ketonuria, and loss of more than 5% of pre-pregnancy weight.

Hyperemesis gravidarum is a serious condition; It is the most common reason for hospitalization in the first half of pregnancy and is only second to preterm labor as a reason for hospitalization in pregnancy.  The effects of HG are widespread, far-reaching and potentially severe for mother and baby.

Etiology

Hyperemesis gravidarum has no clear etiology, but the fact that it is seen in other mammals including monkeys and dogs lends credence in evolutionary terms to some selective advantage.  Some have postulated that morning sickness evolved to prevent the mother from ingesting harmful substances in order to protect the fetus during the most critical time in its development.  Hyperemesis gravidarum appears to be a normal process that has gone out of control.

Factors that may contribute to  HG include:

Human chorionic gonadotropin (hCG):  A rise in the hormone (hCG)  may stimulate upper gastrointestinal (GI) secretions causing nausea and vomiting.  This disturbance may explain the increased incidence of HG seen in multiple pregnancy and molar pregnancy where hCG levels are quite high.

Estrogen: The rise in the hormone estrogen that accompanies pregnancy, may delay gastric emptying due to a decrease in intestinal motility.  Women with a history of HG who undergo fertility treatments have reported similar symptoms to those they experience when exposed to high levels of estrogen during  controlled ovarian hyperstimulation (COH) cycles used in these treatments.  Interestingly, the risk of HG is increased if the gender of the fetus if female.

Thyroid: In two-thirds of patients with HG, the physiological stimulation of the thyroid gland leads to hyperthyroidism, a  condition referred to as gestational transient thyrotoxicosis (GTT).  The majority of studies looking at thyroid function and HG have shown significantly higher levels of thyroxin (T4) and thyroid-stimulating hormone (TSH) in HG patients compared to controls.  In addition, hCG shares a common alpha subunit with TSH and this structural similarity can cause stimulation of the thyroid gland with high levels of hCG.

Helicobacter pylori infection:  The first reported association between Helicobacter pylori (H. pylori) and HG was made in 1998 by Frigo et al.  Helicobacter pylori is a  bacterium that can survive an extremely acidic environment and lives in the stomach.  It commonly associated with chronic gastritis, peptic ulcer disease, and cancer of the stomach.  Despite the high prevalence of stomach colonization in the world population (50%-60%), most individuals are not clinically ill.  The gold standard for making the diagnosis of H. pylori infection is an endoscopic mucosal biopsy of the stomach.  Of more than fourteen prospective case-control studies reporting an association between HG and H. pylori, only one used endoscopy to diagnosis H. pylori.  These authors found that 95% of patients with HG tested positive for H. pylori compared to 50% in the control group.  Treatments for H. pylori in patients with HG focus on eradication of the organism and, thus, alleviation of the symptoms but have not been widely studied.

Genetics: There appears to be a genetic predisposition to HG as one-third of women with HG have a mother who was also affected.  Women who have a sister with HG have an 17 fold increase risk of getting HG themselves.   Several reports on looking for a possible paternal contribution have failed to demonstrate any difference in the incidence of HG with changing paternity.

Psychosocial Factors: Past reports have suggested that HG was, in fact, an expression of maternal resentment towards an unwanted pregnancy.  In addition, several psychosocial factors such as a strong mother dependency, emotional immaturity, anxiety, and stress have been linked to the development of HG.  In recent reports, only a very small minority of cases of HG were found to be related to a psychosocial etiology.  Many instances could be attributed to genetic factors although those patients with a history of anorexia nervosa were at an increased risk of HG.   Most of the psychological symptoms associated with HG are not the cause but are a result of the hardships of the disease.

Others:  Other factors may influence the risk of developing HG and include a previous pregnancy affected by HG, first pregnancy, young age, low pre-pregnancy BMI, fetal triploidy, fetal trisomy 21, hydrops fetalis, and a high-fat diet.  Factors that may protect against developing HG include smoking and a diet rich in seafood, allium vegetables, and water.

The effects of HG are widespread, far-reaching and potentially severe.  They can be categorized by:

Maternal Physical Effects: Electrolyte disturbances including hyponatremia and metabolic ketoacidosis are common complications of HG.  Greater than 60% of patients with HG will develop suboptimal stores of essential vitamins.  This depletion effects levels of thiamine (Vitamin B1), riboflavin (Vitamin B2), Vitamin B6, Vitamin B12 (cobalamin),  Vitamin A, and retinol-binding protein.  Patients with HG are at nutritional risk, and prompt and appropriate corrective therapy is essential before serious and potentially irreversible injury.  Those patients with HG that develop hyponatremia (plasma sodium levels <120 mmol/L) may have a range of clinical features.   Mild hyponatremia may present with anorexia, headache, nausea, vomiting and lethargy.   More severe hyponatremia may result in personality change, muscle cramps and weakness, diminished reflexes, ataxia, confusion, drowsiness, and convulsion.  Those patients with HG that become deficient in Vitamins B12 and B6 risk developing megaloblastic anemia and peripheral neuropathy.  Those HG patients who lack Vitamin B1 risk developing Wernicke’s encephalopathy, a disease that typically occurs only after several weeks of vomiting and is a potentially fatal condition.  In women with HG, the most common presentation of Wernicke’s encephalopathy is apathy or confusion. While this condition is reversible, it should be considered a medical emergency and for those who survive, it can result in  persistent neurological deficits.  Another risk is developing a vomiting induced tear in the esophageal-gastric junction called a Mallory-Weiss tear.  The combination of pregnancy, dehydration, and associated immobility in a woman with HG also increases the risk of venous thromboembolic disease.   In addition, women with HG appear to have an impaired postural stability in the first trimester and are at increase of falling.  Lastly, in one report there was a suggestion that there may be long-term maternal health consequences to having had HG as well.  Those women with HG had an increased risk of developing thyroid cancer that was positively related to the number of HG pregnancies.  However, women with a history of HG had a reduced risk of developing cancer of  the lungs, cervix and rectum.

Maternal Psychosocial Impact: Being inflicted with HG turns an otherwise happy and exciting time in a women’s life into months of misery for her and her family.  It is no surprise that numerous studies have demonstrated that women with HG are at increased risk of suffering from anxiety and depression.  In a study by Poursharif et al. that investigated the psychosocial impact of HG, 80% of women with HG, who were examined, reported an negative attitude about their pregnancy, fear of  a future pregnancy, and psychiatric issues including depression and anxiety.  A more recent report on this topic found that 18% of HG patients suffered post-traumatic stress syndrome (PTSS) following a pregnancy(ies) affected by HG.  This revelation highlights the importance of providing these patients with psychosocial counseling and support early in their disease.

Economic Burden: Hyperemesis gravidarum is the most common cause of hospitalization in the first half of pregnancy. With the exception of preterm labor, HG is the most common pregnancy-related hospitalization.   In 2008, there were more than 160,000 emergency department visits in the Untied States alone that were attributable to HG.  In 2009, there were 22,000 hospitalizations.  Thus, the economic burden of HG came from both increased utilization of medical services as well as time missed from work.   A report by Piwko et al., estimated that in 2012 the overall economic burden of nausea and vomiting to third party payers in the United States was $1.8 billion.

Effects on Newborn:  Hyperemesis gravidarum causes enormous physical and psychological hardships for the mother.  As far as fetal outcomes, less severe nausea and vomiting appears to be protective and improves fetal outcomes that include lower rates of miscarriage, congenital defects, and preterm birth.  On the other hand, the more severe HG invariably leads to significant maternal weight loss and is associated with suboptimal fetal outcomes. These outcomes include  preterm birth, small for gestational age infants, and an increase in length of postnatal hospital stay. Several studies have also reported an increase in fetal and neonatal deaths although this is not a consistent finding.  In a recent Swedish population study by Bolin et al.,  the researchers observed an association between HG and placentation disorders.  These disorders include an increased risk of preeclampsia, placental abruption, and small-for-gestational-age birth babies.  In addition, the recent evaluation of children born from pregnancies affected by HG, showed no abnormalities in intellectual development.  Interestingly, those children born from pregnancies associated with the less severe nausea and vomiting of pregnancy, showed higher non-verbal intelligence scores that positively correlated with the severity of symptoms.  A study by Mullin et al. in 2011,  demonstrated that in utero exposure to HG was associated with an increased risk of depression, bipolar disorder, and anxiety in adulthood.  Several recent reports also suggest that offspring of HG pregnancies have reduced insulin sensitivity as adults.

Hyperemesis gravidarum is a miserable disease with serious short and long term consequences for both mother and baby.  It deserves serious attention so that timely medical and psychosocial resources can be engaged at an early stage.  Treatment options will be discussed in a follow-up post.

References:

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Empowering Fertility: An educational blog for patients & healthcare professionals that empowers individuals to take charge of their fertility. Visit us at http://empoweringfertility.com.

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