Hyperemesis Gravidarum Nursing CE Course

2.0 ANCC Contact Hours AACN Category A

Syllabus

Course Objectives

At the completion of this activity, the learner should be able to:

  1. Demonstrate a basic understanding of the defining characteristics of the disorder hyperemesis gravidarum.
  2. Discuss the principles of anatomy and physiology associated with hyperemesis gravidarum.
  3. Demonstrate knowledge of the theories explaining the pathophysiology of hyperemesis gravidarum.
  4. Discuss the signs and symptoms related to the disorder of hyperemesis gravidarum. 
  5. Identify the individuals most at risk for developing hyperemesis gravidarum in pregnancy.
  6. Describe methods to diagnose hyperemesis gravidarum in pregnancy.
  7. Recognize current treatment options used in hyperemesis gravidarum. 
  8. Identify ongoing literature discussion on the needs for future research on hyperemesis gravidarum in pregnancy.

Purpose statement

The purpose of this continuing education activity is to update the participant on current knowledge regarding the disorder of hyperemesis gravidarum in pregnancy.

Introduction

Nausea and vomiting are common during the first trimester of pregnancy, affecting up to 70% of women who often do not require treatment (Fiaschi, Nelson, Deb, King & Tata, 2019).  Although generally considered benign, these symptoms may impair the patient’s ability to perform daily roles and fulfill obligations adding to the quality of life.  For most individuals affected, the problem resolves during the second trimester, and for 91% of pregnant women completely before 20 weeks of gestation (Trovik & Vikanes, 2019).  Hyperemesis gravidarum (HG) is a complication of pregnancy in which extreme, persistent nausea and vomiting (three or more episodes in 24 hours) occur during pregnancy (Cleveland Clinic, 2016).  Some cases can reach critical severity levels requiring hospital admission and the need for continuous monitoring (Ioannidou, Paanikolaou, Mikos, Mastorakos & Goulis, 2019). Dinberu et al. (2019) cautioned that quality evidence is challenging to procure in low- and middle-income countries, but the prevalence of HG overall in these countries ranges from 0.3% to 10.8%.  Other reports show a prevalence of approximately 0.3-3% in pregnant females (Fiachi et al., 2019; Gabra, 2018; Ioannidou et al., 2019).  It is important for caregivers to understand the factors affecting individuals diagnosed with HG and to advise and respond appropriately to ensure good outcomes for mother and baby.

Anatomy & Physiology

Human chorionic gonadotropin (hCG) levels are expected to rise during pregnancy.  hCG is a pregnancy hormone secreted by the placental syncytiotrophoblast cell layer.  The syncytiotrophoblast is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish circulation for nutrient and gas exchange between the embryo and the mother.  Insufficient circulation has been linked to deficient fetal growth and various placental, uterine, and fetal functions.  Abnormal levels of hCG have previously been associated with adverse pregnancy outcomes such as fetal loss, preeclampsia, preterm delivery, and fetal growth restriction (Korevaar et al., 2015).  

Normal hCG levels in early pregnancy double every 48-72 hours, ranging from 10,000 - 25,000 mIU/ml.  The levels peak at about ten weeks when they may be as high as 60,000 mIU/ml.  Over the next few weeks, hCG concentration will drop and stabilize at about 15,000 mIU/ml, where it will remain through the end of the pregnancy (Cleveland Clinic, 2016).  

hCG is necessary to maintain a pregnancy because it promotes progesterone production for approximately three to four weeks following pregnancy implantation.  hCG interacts with the LhCG receptor on the ovary and helps maintain the corpus luteum during the beginning of pregnancy. This group of cells helps produce the hormone progesterone during early pregnancy. This process allows the corpus luteum to secrete the hormone progesterone during the first trimester.  Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus.  The corpus luteum will continue to produce progesterone until the fetus is producing adequate levels to sustain the pregnancy, which happens between seven and nine weeks of pregnancy.  Although hCG is often blamed for the nausea and vomiting associated with early pregnancy, without it, the pregnancy would not be successful from the start (Smith, 2017).

Pathophysiology

HG has a complex interaction of biological, psychological, and sociocultural factors supported by many theories.  The exact cause of HG is not entirely understood, which is why so many theories have been suggested to explain this disorder.  In the early 1900s, theories for hyperemesis were ruled by psychological themes such as rejection of pregnancy due to embarrassment about sexual relations or fears of childbirth and motherhood (National Organization for Rare Disorders [NORD], 2015).   This may no longer be current thinking, but the psychological and social effects of hyperemesis are likely underestimated.  Pregnant women with HG, particularly severe HG, are at potential risk for psychological stress.  The severity of vomiting is linked with social dysfunction, anxiety, sleep disorders, and severe depression (Gabra, 2018).  Aksoy et al. (2015) found the current prevalence of moderate-severe depression disorder in patients with HG was 53.9%. Questions arose during the analysis of the study regarding whether the depression experienced was directly related to nausea and vomiting.  The researchers found the tool they used might have inflated the results due to questions asked which included “loss of pleasure, loss of energy, changes in sleep pattern, changes in appetite, tiredness or fatigue, etc.”  The participants may have related these experiences to nausea and vomiting rather than any resulting depression (Aksoy et al., 2015).  

Thyroid function is altered during normal pregnancy.  An increase in the thyroxine-binding globulin (TBG), induced by estrogens, leads to a decrease in free thyroxine concentration.  This negative feedback on the pituitary incites an increase in thyroid stimulating hormone (TSH) secretion and hyperstimulation of the thyroid. Thyrotoxic crisis during pregnancy is rare but the physiological processes described above place the mother and fetus in real danger, especially in patients with a pre-existing condition of hyperthyroidism (Hussein, 2017).    

Additionally, women with HG often have high hCG levels that cause brief increased activity in the thyroid gland.  The rising levels of hCG activate the TSH receptors on the thyroid gland.  This stimulation of the thyroid gland can lead to signs/symptoms of hyperthyroidism, such as palpitations, shortness of breath, nausea, vomiting, and diarrhea due to the increased metabolic rate. Another mechanism present is an increase in iodine clearance which leads to hyperstimulation of the gland to compensate for a perceived deficiency. Levels of hCG usually peak in the first trimester, and thyroid function normalizes by the 18th week with no further intervention.  hCG may not cause HG alone, but it may be indirectly involved due to the stimulation of the thyroid (Hussein, 2017).  

Other theories used to explain HG are genetic predisposition, avoidance of dangerous dietary substances that may have caused harm to the fetus (such as pathogenic microorganisms in meat products and toxins in plants), and the effects of hormone levels (such as estrogen) and/or vitamin B deficiencies (Agmon, Sade, Pariente, Rotem & Weintraub, 2019; NORD, 2015).  Additionally, hyperthyroidism, gastroesophageal reflux in association with gastric dysrhythmias, H. pylori infections of the stomach, and disturbances in carbohydrate metabolism have been suggested as etiologies for HG (NORD, 2015).  

Many of these theories are based on symptoms that HG itself might cause.  For example, women diagnosed with HG are often unable to tolerate typical food and fluid intake in pregnancy and might develop vitamin deficiencies, thyroid imbalance, and other metabolic disturbances as a result. This rationale makes the investigation of HG more difficult when the caregiver cannot discern which came first; the HG or the disturbance and imbalance (Hill, 2015).  

Risk/protective factors

Family history is significant for HG since genetic predisposition in the development of severe nausea and vomiting of pregnancy has been documented (Ioannidou et al., 2019).  Family history significantly increases the risk to daughters and sisters of women with a history of HG.  Researchers also report that a history of HG in a previous pregnancy increases the risk of developing or increasing the duration of HG (Hill, 2015).  Evidence also supports a genetic predisposition to nausea and vomiting when multiple fetuses are present during pregnancy, the woman has had no previous completed pregnancies (nulliparity), and during a first-time pregnancy (Hill, 2015; Ioannidou et al., 2019).   

Extreme nausea and vomiting during pregnancy might also indicate hydatidiform mole (abnormal tissue growth that is not a true pregnancy) (Cleveland Clinic, 2016).  Gestational trophoblastic disease (GTD) or molar pregnancy does not cause HG; however, women with GTD may have symptoms such as severe nausea and vomiting that resemble HG (Hill, 2015; Wilson, 2018).

Additionally, researchers have reported that certain factors may be associated with an increased risk of developing or increasing the duration of HG including younger maternal age, obesity, allergies, and a restrictive diet (Hill, 2015; NORD, 2015). 

Signs and symptoms

HG has a classic clinical presentation of persistent nausea and intractable vomiting (three or more episodes in 24 hours) which occur during pregnancy (Cleveland Clinic, 2016).  Patients often indicate that certain stimuli, in particular smells, provoke vomiting and aggravate the disorder. Scents are thought to be a strong trigger for nausea and vomiting in pregnancy (van Vliet et al., 2018).  Other signs and symptoms may include excessive salivation, fatigue, weakness, and dizziness (Ogunyemi, 2017).  HG is the most severe form of pregnancy-induced nausea and vomiting and is further characterized by ketosis and significant weight loss (greater than 5% of pre-pregnancy weight) (MedScape, 2017).  

Most HG patients also will have hyponatremia, hypokalemia, and a low serum urea level.  Many studies agreed that HG may be responsible for a range of complications due to malnutrition, dehydration, electrolytes and acid-base imbalances, significant weight loss, and even death (Agmon et al., 2019; Fiaschi et al., 2019; Medscape, 2017).  Pregnant women have an increased need for the essential nutrient thiamine.  When HG occurs, thiamine depletes rapidly, which may lead to Wernicke’s Encephalopathy (WE).   WE is most commonly found in alcoholic patients.  The early signs of WE are nausea, vomiting, and double or blurred vision.  As the condition progresses, affected patients will experience a staggering gait, confusion, and agitation (Oudman et al., 2019).

Other notable signs and symptoms associated with HG were described by Dean, Bannigan, and Marsden (2018).  The authors found that social isolation and the inability to care for self and others changed the pregnant woman’s role fulfillment.  This led to adverse psychological effects, such as depression, anxiety, guilt, and loss of self.  In extreme cases, a sense of dying, suicidal ideation, or desire to terminate the pregnancy were found (Dean et al., 2018).

Diagnosis

A care provider should ask about symptoms, take a medical history, and perform a physical exam.  In most cases, the physical examination provides enough information to diagnose HG.  The history and exam are looking for the most common signs and symptoms of HG.  The patient will be asked about feeling nearly constant nausea, loss of appetite, vomiting more than three or four times per day, becoming dehydrated, feeling light-headed or dizzy, and/or weight loss due to nausea or vomiting (Cleveland Clinic, 2016; Wilson, 2018).

In addition, certain lab tests might be done such as a metabolic panel, complete blood count, and urinalysis (Cleveland Clinic, 2016).  Niemeijer et al. (2014) completed a literature review on diagnostic lab tests to discern any commonalities, but none were found for a definitive diagnosis of HG.  The literature does show the most substantial support for weight loss above 5% of body weight (or 3 kg/6.6 lb) as a significant criterion for diagnosis. Information was found in studies on ketonuria, white blood cell count, estradiol levels, TSH, and free thyroxine 4 (T4) that were also represented.  However, the use of multiple biomarkers continues for diagnostic purposes depending on the care provider (Niemeijer et al., 2014).

Treatment/Management

Dietary management

Management options for simple morning sickness include various home remedies, such as snacking throughout the day on dry foods (like crackers) and sipping ginger ale to help relieve nausea.  Small frequent meals and emotional support can also be helpful to patients experiencing nausea and vomiting in pregnancy.  Additional dietary management techniques for nausea include drinking small amounts to avoid dehydration, trialing different kinds of fluids, avoiding fatty or spicy foods, and avoiding an empty stomach. Vitamin B6 and/or ginger teas and chews might also help to relieve symptoms (Cleveland Clinic, 2016; Mayo Clinic, 2018).  The GI symptoms of motion sickness and hyperemesis are similar, so preventive measures are often comparable.

Ginger has been studied as a therapy to treat hyperemesis. The effectiveness of ginger is dependent on its aromatic, anti-flatulent, and absorbent characteristics.  It acts on the GI tract to increase motility, and its absorbent property may decrease stimuli to chemoreceptors in the medulla that send stimuli to the emetic center of the brain stem. Ginger may also block nausea feedback and has been successfully described as an adjunct to chemotherapy treatment for nausea and vomiting (Marx et al., 2017; Wegrzyniak, Repke, & Ural, 2012).  

Lifestyle management

Lifestyle adjustments can be of equal value when managing nausea and vomiting.  The nurse should encourage the patient to eat well when she is feeling her best or when hungry to enhance overall nutrition.  In some cases, treatments for mild nausea and vomiting in pregnancy may include bed rest, avoiding foods and odors that may trigger an episode of nausea or vomiting. Sensitivity to smells is common, so the nurse can recommend that she substitute some cold meals or cook in well-ventilated areas.  Pregnant patients can ask for help from family and friends to avoid cooking responsibilities when possible. The nurse should instruct the patient to lie down when their nausea is severe and avoid stress which can increase the presentation of their symptoms.  Prenatal vitamins can be taken when the patient is feeling less nauseous rather than a consistent time of day and physical activity should be consistent but moderate to avoid overexertion (Cleveland Clinic, 2016; Mayo Clinic, 2018).  

Acupressure/Acupuncture

Preventive measures may include an acupressure wristband. Acupuncture may also be offered as an adjunct therapy to conventional treatment. Acupuncture and/or acupressure on the point above the wrist on the palmar side (See figure 1 below) have been found to prevent some types of nausea and vomiting when compared to placebo groups. 

Acupuncture therapy has no documented cases of teratogenic side effects, and patients may appreciate the option of avoiding medication (Karim, Dilley, & Cheung, 2019). If nausea and vomiting persist despite these strategies, antiemetic drug therapy may be the next step.  

Medication Therapy

Medicine to prevent nausea is used when vomiting is persistent and poses possible risks to the mother or baby.  Taking medications during pregnancy may be distressing for women. A persistent belief that they will hurt their baby may need to be clarified to avoid compliance issues.  Patients refusing medication therapy, when indicated, may result in their worsening condition. It is important for mothers to understand the risks of untreated HG on herself and her child including chronic dehydration, malnutrition, metabolic and emotional stress, as well as reduced mobility. Several drugs are used as an antiemetic to control nausea and vomiting during pregnancy.  The safety of any medication prescribed should be weighed carefully and collaboratively by the healthcare team (specifically the prescriber) and the patient. The inherent risks of the condition (HG) should be weighed against the risks of the medication. In 2014, the US Food and Drug Administration (FDA) removed the older system of ranking medications for pregnant women (Category A, B, C, D, and X), and now requires detailed specific information about pregnancy safety (including during labor and delivery), safety while breastfeeding, and safety for females and males of reproductive potential (US FDA Center for Drug Evaluation and Research, 2018). 

Treatment during early pregnancy usually involves pyridoxine (vitamin B6) and antihistamines, which may be administered separately or as a combination drug (pyridoxine/doxylamine succinate [Diclegis, Bonjesta]).   Pyridoxine safely improves nausea with minimal side effects, so it is typically the initial drug treatment. Doxylamine succinate (Unisom) is an over-the-counter antihistamine often sold as a sleep aid that is also used to help with nausea and vomiting in pregnancy.  Both of these medications were previously considered pregnancy Category A by the FDA (considered safe). The primary mechanism of antihistamines in the treatment of nausea and vomiting of pregnancy is direct inhibition of histamine at the H1 receptor.  The secondary mechanism is an indirect effect on the vestibular system by decreasing the stimulation of the vomiting center.  Doxylamine succinate (Unisom) can cause drowsiness, and patients are cautioned to avoid driving after taking this drug.  Antihistamines can also cause dry mouth and dry nasal passages.  Additionally, antihistamines should be avoided in women taking ondansetron (Zofran) or other medications that prolong the QT interval (Smith, Clark, & Fox, 2019).

Ranitidine (Zantac) and famotidine (Pepcid) are histamine H-receptor antagonists developed for the treatment of gastroesophageal reflux disease (GERD). Both were previously Category B medications (likely safe). They will sometimes work for the pregnant patient experiencing nausea and vomiting if the nausea is triggered by stomach or intestinal problems (Hyperemesis Education & Research [HER] Foundation, 2019). 

Antiemetics are usually only prescribed in severe situations, such as if a woman has HG or where nausea and vomiting interfere with everyday life.  These drugs are prescribed only after weighing their advantages against their potential hazards. Antiemetic drugs may be prescribed in the first trimester of gestation and have not been proven to cause detrimental effects to the developing fetus (MD health.com, 2019; Wegrzyniak et al., 2012).  The drugs most often prescribed include metoclopramide (Reglan), prochlorperazine (Compazine), , promethazine (Phenergan), ondansetron (Zofran), and cyclizine (Marezine). Metoclopramide (Reglan) is one of the most commonly prescribed medicines for nausea and vomiting. It was previously an FDA pregnancy Category B (likely safe) and is not associated with any congenital fetal malformations. Prochlorperazine (Compazine) and promethazine (Phenergan) were previously Category C drugs (risk cannot be ruled out), and ondansetron (Zofran) was a Category B drug (likely safe).  Animal studies with the use of cyclizine (Marezine) have revealed evidence of malformations (e.g., cleft palate, cephalic abnormalities) at doses above 25 to 50 mg/kg/day. There are no controlled data in human pregnancy, although this drug was previously categorized as pregnancy Category B (likely safe) by the FDA (Cleveland Clinic, 2016; Fiaschi et al., 2019; Kaunitz, 2019; Wilson, 2018). 

If a woman cannot take medicines by mouth, the drugs might be administered via IV or a suppository. If all other measures fail, corticosteroids are used as a last resort for severe nausea and vomiting. Although the symptoms improve dramatically with the use of corticosteroids, this therapy should not be initiated before ten weeks of gestation secondary to associated congenital malformations like cleft palate in neonates. Prednisone (Rayos) was previously a Category D drug (some risk) and methylprednisolone (Medrol) was a Category C (risk cannot be ruled out) (HER Foundation, 2019).

Restoring Homeostasis

Fiaschi et al. (2019) described four main categories identified for treatment based on care setting and severity of HG: 1) primary care diagnosis only, 2) treatment in primary care, 3) early hospital admissions (before 20 weeks’ gestation), and 4) late hospital admissions. For those individuals diagnosed with HG and demonstrating compromised physical functioning, immediate hospitalization to restore fluids and replace electrolytes by infusing medication and fluids intravenously is the treatment of choice. Food should not be given orally until vomiting stops, and dehydration has been corrected. Instead, nutrition may be provided by enteral or parenteral routes. A pregnant woman needs to maintain fluid intake. Pregnancy increases the demand for hydration to form amniotic fluid, produce extra blood, build new tissues, transport nutrients, improve digestion, and eliminate wastes or toxins (Torborg, 2015).  

The type of treatment that is required depends on how ill a woman becomes. Enteral feedings via nasogastric tube can provide needed fluids and nutrients to patients experiencing HG, but the literature provides mixed information regarding its overall efficacy.  For example, Grooten et al. (2017) described early enteral tube feeding in pregnant women diagnosed with HG as not improving birth weight or overall fetal outcomes. Many women discontinued tube feeding due to discomfort, indicating that it was poorly tolerated as an early treatment of HG. Van Vliet et al. (2018) discussed perceptions of women not treated with tube feedings who shared they felt it might have been beneficial to prevent weight loss, ensure essential nutrition to the fetus, and reduce vomiting due to an empty stomach. No definitive information was found to support the benefits outweighing the risk/inconvenience of enteral feedings, and it remains a treatment option for women experiencing HG (Van Vliet et al., 2018).

Intravenous (IV) fluids might be needed if a woman continues to vomit throughout pregnancy. In severe cases, the woman might require hospitalization. IV fluids should be provided to replenish the lost intravascular volume. Rehydration, along with the replacement of electrolytes, is crucial in the treatment of hyperemesis.  Normal saline or lactated ringers (Hartmann solution) are suitable solutions; potassium chloride can be added as needed to correct hypokalemia common in HG (Wegrzyniak et al., 2012).  IV fluids may be discontinued when a woman can take in fluids orally again (Cleveland Clinic, 2016).  

The most severe cases of HG might require that complex, balanced solutions of nutrients be given via IV as total parenteral nutrition (TPN) throughout pregnancy. This treatment would be indicated in prolonged cases of HG when a concern for long-term outcomes based on loss of hydration and nutrition were evident in hospitalized pregnant patients. Peled et al. (2014) found that TPN support during early pregnancy was associated with a decreased risk for perinatal morbidity in patients experiencing HG.  Vitamin supplementation (particularly vitamin B6, vitamin C, and thiamine) may also be recommended. Thiamine supplementation is explicitly suggested to prevent WE after exhaustion of B-vitamin reserves, in particular thiamine (Fejzo, 2015).  

Evidence-based nursing practice/implications for nursing

After vomiting subsides, affected patients should receive nutritional supplementation to calm the nausea. Care providers should then slowly reintroduce fluids and small, frequent meals into the diet. Meals should consist of foods high in carbohydrates and low in fat (Trovik & Vikanes, 2019).  

Trovik & Vikanes (2019) recommended that improved treatment for women suffering from nausea and vomiting in pregnancy is needed.  Strategies include better awareness of the impact this condition has on a pregnant woman's quality of life and educating care providers regarding medication best practices to relieve symptoms earlier. It is important to not only decide on the correct medication(s), but also to make sure a medication is being tolerated and taken correctly for optimal effectiveness. Early pregnancy symptoms are challenging to manage as symptoms generally increase until the end of the first trimester. Many variables affect responsiveness to medications such as hydration and nutritional status, duration of symptoms, and interactions with other medications. These must be considered when assessing a mother’s response.  Additionally, minimizing changes to doses and regimen when women are improving can prevent relapse, especially during initial recovery (Trovik & Vikanes, 2019).

Van Vliek et al. (2018) interviewed individuals affected by HG. Interviewees emphasized the importance of early recognition of the severity of HG, increasing caregivers’ knowledge on HG, early medical intervention, and nasogastric tube feeding (when appropriate). Participants also valued a private room in the hospital to avoid exposure to environmental stimuli which increased symptoms (odors, noise, stress).  Additionally, discussion of treatment options, more possibilities of home-based treatment, psychological support during HG and after childbirth, and more uniform information and policies regarding HG treatment were outcomes of qualitative interviews to improve evidence-based practice (van Vliek et al., 2018).

Future research/directions 

Although the term HG is commonly used in clinical practice, there are no clear and widely accepted diagnostic criteria to define HG.  A classification system differentiating HG by the degree of severity would be helpful to care providers to establish clinical guidelines for care procedures.  Currently, the severity of the case is identified and treated at the discretion of the care provider, which can lead to inconsistencies in protocols and prescribed treatment plans.  Maternal and child health may be affected by possible adverse effects and complications of HG.  These consequences have a financial impact on the individual and healthcare systems (Fiaschi et al., 2019).  Creating care pathways with standardized approaches can establish continuity of care and may help to avoid additional healthcare costs for unnecessary hospitalizations or prescriptions. Further research is needed to establish whether a standardized approach can lead to more cost-effective care and improve the course of HG and outcomes for HG patients and their children (van Vliek et al., 2018).

More effective antiemetic drugs approved for use in nausea and vomiting in pregnancy would assist the pregnant female in maintaining adequate hydration and nutrition throughout the pregnancy. More effective and safe medications to alleviate these signs and symptoms are needed to improve the pregnancy experience (Trovik & Vikanes, 2019).   

Finally, the association between HG and adverse pregnancy outcomes remains an issue of considerable controversy.  This applies to both maternal complications and neonatal adverse outcomes such as placental dysfunction disorders (e.g., intrauterine growth restriction, preeclampsia, and stillbirth). Given this lack of clarity, the association between HG and adverse pregnancy outcomes should be further researched. The degree of severity associated with HG diagnosis has not been consistently described in the literature, and no clear definitions exist.  Investigating whether the severity of the disorder is clinically significant and related to outcomes with consistent guidelines to document patient cases would be an important step (Agmon et al., 2019).

References

Agmon, N., Sade, S., Pariente, G., Rotem, R., & Weintraub, A.Y. (2019).  Hyperemesis gravidarum and adverse pregnancy outcomes.  Archives of Gynecology & Obstetrics, 300(2), 347-353. doi: 10.1007/s00404-019-05192-y

Aksoy, H., Aksoy, U., Karadag, O.I., Hacimusalar, Y., Acmaz, G., Aydut, G., Cagli, F., Yucel, B., Aydin, T., & Babayigit, M.A. (2015).  Depression levels in patients with hyperemesis gravidarum:  A prospective case-control study. Springer Plus, 4(34). doi: 10.1186/s40064-015-0820-2

Cleveland Clinic (Nov. 4, 2016).  Hyperemesis Gravidarum (Severe Nausea & Vomiting during Pregnancy). Retrieved from https://my.clevelandclinic.org/health/diseases/12232-hyperemesis- gravidarum-severe-nausea--vomiting-during-pregnancy

Dean, C., Bannigan, K., & Marsden, J. (2018).  Reviewing the effect of hyperemesis gravidarum on women’s lives and mental health.  British Journal of Midwifery, 26(2), 109-119. doi:10.12968/bjom.2018.26.2.109

Dinberu, M.T., Mohammed, M.A., Tekelab, T., Yimer, N.B., Desta, M., & Habtewold, T.D. (2019). Burden, risk factors and outcomes of hyperemesis gravidarum in low-income and middle-income countries (LMICS):  Systematic review and meta-analysis protocol. BMJ Open, 9(4).  doi: 10.1136/bmjopen-2018-025841.

Fejzo, M.S. (2015). Hyperemesis Gravidarum. Retrieved from https://rarediseases.org/rare-diseases/hyperemesis-gravidarum/

Fiaschi, L., Nelson, P.C., Deb, S., King, R., & Tata, L. (2019).  Clinical management of nausea and vomiting in pregnancy and hyperemesis gravidarum across primary and secondary care:  A population-based study.  BJOG:  An International Journal of Obstetrics & Gynaecology, 126(10), 1201-1211.  doi: 10.111/1471-0528.15662

Gabra, A. (2018). Complications of hyperemesis gravidarum: A disease of both mother and fetus, Review article.  Critical Care Obstetrics and Gynecology, 5(1).  

Grooten, I.J., Koot, M.H., van der Post, J.A., Bais, J.M., Ris-Stalpers, C., Naaktgeboren, C.,… Painter, R.C. (2017).  Early enteral tub feeding in optimizing treatment of hyperemesis gravidarum:  The maternal and offspring outcomes after treatment of hyperemesis by refeeding (MOTHER) randomized controlled trial.  The American Journal of Clinical Nutrition, 106(3), 812-820. doi: 10.3945/ajcn.117.158931 

Hill, D.A. (2015).  Molar pregnancy (gestational trophoblastic disease).  Hyperemesis Education & Research (HER) Foundation.  Retrieved from https://www.helpher.org/hyperemesis-gravidarum/diagnosis/molar-pregnancy.php

Hyperemesis Education & Research (HER) Foundation. (2019). Medications.  Retrieved from http://hyperemesis.org/hyperemesis-gravidarum/treatments/medications.php

Hussein, K.S. (2017).  Thyroid functions with cases of hyperemesis gravidarum in Saudi women. International Journal of Pharmaceutical Research & Allied Sciences, 6(2), 98-106.   

Ioannidou, P., Papanikolaou, D., Mikos, T., Mastorakos, G., & Goulis, D.G. (2019). Predictive factors of hyperemesis gravidarum:  A systematic review.  European Journal of Obstetrics & Gynecology & Reproductive Biology, 238, 178-187. doi: 10.1016/j/ejogrb.2019.04.043

Karim, F., Dilley, J., & Cheung, E. (2019).  A review of acupuncture in obstetrics and gynaecology. Obstetrician & Gynaecologist, 21(3), 209-214.  doi:10.1111/tog.12574

Kaunitz, A.M., (2019).  Metoclopramide during Early Pregnancy: How Safe? 

 MedScape.     Retrieved from https://www.medscape.com/viewarticle/709802

Korevaar, T.I, Steegers, E.A., de Rijke, R.B., Schalekamp-Timmermans, S., Visser, W.E., Hofman, A., …., Peeters, R.P. (2015). Reference ranges and determinants of total hCG levels during pregnancy:  The generation R study.  European Journal of Epidemiology, 30(9), 1057-1066. doi:10.1007/s10654-0150039-0  

Marx, W., Ried, K., McCarthy, A.L., Vitetta, L., Sali, A., McKavanagh, D., & Isenring, L. (2017). Ginger—Mechanism of action in chemotherapy-induced nausea and vomiting: A review. Critical Reviews in Food Science and Nutrition, 57(1), 141-146. doi: 10.1080/10408398.2013.865590

Mayo Clinic (Sept. 22, 2018).  Morning Sickness.  Retrieved from https://www.mayoclinic.org/diseases-conditions/morningsickness/symptoms-causes/syc-20375254 

MD health.com (2019).  Is Antiemetic Safe for Your Pregnancy?  Retrieved from       https://www.md-health.com/Antiemetic-in-Pregnancy.html

National Organization for Rare Disorders (NORD). (2015). Hyperemesis gravidarum. Retrieved from https://rarediseases.org/rare-diseases/hyperemesis-gravidarum/

Niemeijer, M.N., Grooten, I.J., Vos, N., Bais, J.M, van der Post, J.A., Mol, B.W., Roseboom, T.J., Leeflang, M.M., Painter R.C. (2014).  Diagnostic markers for hyperemesis gravidarum:  A systematic review and meta-analysis.  American Journal of Obstetrics and Gynecology, 211(2), 150.e1-15. doi: 10.1016/j.ajog.2014.02.012

Ogunyemi, D.A. (Jan. 4, 2017).  Hyperemesis gravidarum.  In Medscape.  Retrieved from https://emedicine.medscape.com/article/254751-overview

Oudman, E., Wijnia, J.W., Oey, M., van Dam, M., Painter, R.C., & Postma, A. (2019). Wernicke’s encephalopathy in hyperemesis gravidarum: A systematic review.  European Journal of Obstetrics & Gynecology & Reproductive Biology, 236, 84-93. doi: 10.1016/j.ejogrb.2019.03.006

Peled, Y., Melamed, N., Hiersch, L., Pardo, J., Wiznitzer, A., & Yogev, Y. (2014).  The impact of total parenteral nutrition support on pregnancy outcome in women with hyperemesis gravidarum.  Journal of Maternal-Fetal & Neonatal Medicine, 27(11), 1146-1150. doi: 10.3109/14767058.2013.851187

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