By: Andria M. Keating Research Project FACS 461

1. Severe Hyperemesis Gravidarum: Total Parenteral Nutrition Predisposing Factors for Infant Nutritional Deficiencies By: Andria M. Keating Research Project FACS 461

2. Introduction: • In the United States there are 80,000 reported annual cases of Hyperemesis Gravidarum (HG) • Severe Hyperemesis Gravidarum occurs in 1% of pregnancies • Hyperemesis gravidarum is extreme, persistent nausea and vomiting during pregnancy that may lead to dehydration and the inability to adequately meet caloric intake • Hyperemesis Gravidarum can occur usually within the first trimester of pregnancy • Believed to affect one in fifty women during pregnancy • The is no known cause/cure for HG

3. Signs and Symptoms • Anemia • Body odor (from rapid fat loss & ketosis) • Confusion • Decreased urination • Dehydration • Dry, furry tongue • Excessive salivation • Extreme fatigue • Fainting or dizziness • Food aversions • Gall bladder dysfunction • Headache • Hypersensitive gag reflex • Increased sense of smell • Intolerance to motion/noise/light • Jaundice • Ketosis • Liver enzyme elevation • Loss of skin elasticity • Low blood pressure • Overactive thyroid or parathyroid • Pale, waxy, dry skin • Rapid heart rate • Rapid weight loss of 5% or more (from pre-pregnancy weight) • Secondary anxiety/depression • Vitamin/electrolyte deficiency • Vomiting of mucus, bile or blood

4. Diagnosis Criteria • Normal Nausea/Vomiting VS. Hyperemesis Gravidarum

5. Hyperemesis Gravidarum • http://www.youtube.com/embed/MGOqqbBCWg8

6. Treatments: • Intravenous fluids (IV) – to restore hydration, electrolytes, vitamins, and nutrients • Tube feeding: Nasogastric – restores nutrients through a tube passing through the nose and to the stomach • Percutaneous endoscopic gastrostomy – restores nutrients through a tube passing through the abdomen and to the stomach; requires a surgical procedure • Medications – metoclopramide, antihistamines, and anti-reflux medications • Bed Rest • Acupressure • Herbs – ginger or peppermint • Homeopathic remedies are a non-toxic system of medicines. Hypnosis

7. Total Parenteral Nutrition • TPN is a way of supplying all the nutritional needs of the body by bypassing the digestive system and dripping nutrient solution directly into a vein. Your TPN may include a combination of sugar and carbohydrates (for energy), proteins (for muscle strength), lipids (fat), electrolytes, and trace elements • TPN will drip through a needle or catheter placed in your vein for 10 to 12 hours, once a day or five times a week. • Electrolytes include: sodium, potassium, chloride, phosphate, calcium, and magnesium. • Trace elements include: zinc, copper, manganese, and chromium. • Electrolytes are important for maintaining almost every organ in your body. They help your heart, muscles, and nerves to work properly and keep you from becoming dehydrated.

8. Tpn: Pharmacist • Jeff Johnson, PharmD

9. Concerns for TPN use in Pregnant Women: • Fat Soluble Vitamins: Vitamin A,D,E,K-Toxcities • re-feeding and underfeeding syndrome- severely malnourished patients may result in "refeeding syndrome" in which there are acute decreases in circulating levels of potassium, magnesium, and phosphate • Aluminum found in TPN solutions • Precipitates that may form in solution: If the bag is not filtered into the PICC line than the potential for fatal complications exist • Infection :Catheter-related sepsis occurs in about ≥ 50% of patients. Glucose abnormalities (hyperglycemia or hypoglycemia) or liver dysfunction occurs in > 90% of patients. • Mechanical complications-placement of a central venous catheter. Improper placement may cause pneumothorax, vascular injury with hemothorax, brachial plexus injury or cardiac arrhythmia. • Metabolic bone disease, or bone demineralization (osteoporosis or osteomalacia), develops in some patients given TPN for > 3 mo. • Gallbladder complications include cholelithiasis, gallbladder sludge, and cholecystitis. • Volume Overload/ Abnormalities in electrolytes/mineral • Blood clot starts in IV site and breaks off and goes to lungs

10. TPN Complications:

11. Literature reviews: • Identified Possible Causes/Influences for HG • Hormonal Imbalances-human gonadotropin • Vitamin B Deficiency • Hyperthyroidism • GERD • Helicobacter PyloriInfections • Psychological factors • Disturbances in Carbohydrate Metabolism • Nerve found in pelvic diaphragm • Twin and molar pregnancies

12. Literature Reviews: • Maternal Complications: Short-Term • Pre-term delivery <37 weeks gestational age • Reduced Pregnancy weight gain (<5.5 lbs.) • Pregnancy induced Hypertension • Renal Failure • Deep venous thrombosis • Hypoglycemia • Jaundice • Postpartum disorder/ Post traumatic stress • Vasospasms of cerebral arteries • Splenic avulsion • Wernicke’s encephalopathy • Maternal Death

13. Literature Reviews: • Fetal Complications: Short-term • Lower birth weights < 5lbs. • Organs not fully mature • Low Apgar Scores- tests taken within 5 minutes after birth to assess baby’s condition • Fetal death • Small for gestational age <10th percentile • Congenital Heart Disease • Integumentary abnormalities • Shorter length • Undescended Testicles- higher risk of testicular cancer later in life • Hip dysplasia • Large for gestational age • Neural tube defects • Central Nervous System • Malformation/ skeletal malformation

14. Fetal Programming: • Definition of fetal programming that relates adjustments made during fetal life in response to adverse changes in the biological environment with permanent consequences that may have been advantageous in fetal life but confer disease after birth. One study suggests a possible change in the fetus metabolic structure. • http://abcnews.go.com/Health/video/fetal-programming-14021547

15. Literature Reviews: • Women that used TPN throughout pregnancy have delivered premature or under birth weight babies. The researchers studied ten women who were on parenteral nutrition therapy, of which nine women delivered at the 36 week mark or beyond with positive outcomes. • All women who had received total parenteral nutrition showed a reversal of the catabolic state; respiratory quotient values greater than 1.0 indicated lipogenesis and an anabolic state; along with shifting from fat to carbohydrate and protein substrate utilization. • Thiamine (B1) deficiency has been found in as many as 60% of HG patients. A woman who has HG is more likely to develop thiamine deficiency due to an increased demand for glucose metabolism, added to the inability to tolerate sufficient food and vitamin/mineral supplements. The cerebral progression of thiamine deficiency resulting in Wernicke’s encephalopathy has been discovered in 33 cases within the last 20 years.

16. Literature reviews: • The study on TPN and HG sufferers discovered an increased chance of seeking an early termination of pregnancy (TOP) among participants of the study (Aubry et al., 2005). A helpline for HVP conducted a survey of 3,201 callers of which 413 had considered TOP and then 108 of the women went through with TOP. • Conversely, there is no evidence to support the use of TPN and it should only be used as a fallback when all other treatments have failed. The associations of severe complications such as thrombosis, metabolic disturbances and infection are reasons the study find it important to use total parenteral nutrition as a last resort. The study expresses the interest of further studies needed to further investigate complications that may arise due to total parenteral nutrition support.

17. Lit. Review Problems • Small population studies • No studies completed after first year of life for the infant • No studies look at nutritional stores of the infant at birth • Researchers believed there are positive associations with participants on TPN solutions and the increase of TPN complications. The researchers stated the benefits need to be weighed against potential for complications. At this time no studies have been performed on hyperemetic mothers treated with TPN.

18. Problem Statement • Existing research studies have associated infants of women who experienced HG having complications of lower birth weights, small for gestational age, and born prematurely. Studies have proven women that have had subsequent hospitalizations for HG have the highest rates of low birth weights compared to those experiencing HG for the first time. There are no studies establishing the long-term effects that HG and the use of total parenteral nutrition may have exposed the off spring to nutritional deficiencies. The problem exists that no long-term follow-up studies have been done to date on children born to hyperemetic women. There is unknown knowledge of TPN solutions providing adequate nutrition for the mother and the fetus. The lack of long-term effects of total parenteral nutrition during serve HG could potentially put the fetus at risk for chronic diseases later in life (Fetal Programming).

19. Specific Aims: • •To determine the maternal and fetal outcome and nutritional stores of participants experiencing severe HG with treatment of total parenteral nutrition. • •To determine association between infants of hyperemetic mothers and the exposure to nutritional deficiencies due to total parenteral nutrition treatment. • •To determine the long-term health complications of infants from hyperemetic mothers.

20. Significance: • This study will be necessary to research because of the lack of knowledge concerning the long-term complications that result from infants born from hyperemetic women. The role of Total Parenteral nutrition in providing enough nutritional support for maternal and fetal needs to be further explored. TPN use needs to be evaluated to determine if the infant is placed at greater risks for chronic diseases. Research is beginning to suggest that the prolonged malnutrition and dehydration in the mother puts the unborn child at risk for chronic diseases such as diabetes and heart disease later in life. At this time it is important to determine the correlation between the condition and the potential for fetal programming as there are 80,000 women who experience HG each year.

21. Methodology: • Longitudinal observational prospective cohort study-observational study is based upon clinical and field observations due to ethical concerns. • The observational study will observe for long-term complications for infants of hyperemetic women treated with total parenteral nutrition during pregnancy. • Research Team: Pediatrician, Pharmacists, Registered Dietitian, and a Statistician • The study will be approved by the Institutional Review Board of Health Sciences at University of Virginia • The participants will sign a consent form to participate in the study that will allow release of all medical records (Mother/Child).

22. Methodology: • . Participants will be selected from a database on the Hyperemesis Education Research Foundation website: http://www.helpher.org/mothers/ • The website has a database of women that have experienced Hyperemesis during pregnancy due to referral from their physician. Advertisement for the study will be placed on website’s homepage. Interested participants will complete a survey that requires them to answer questions. • A sample size of 100 participants will be chosen and sent an informational email to the registered email account listed on database. • The maternal nutritional records throughout pregnancy will be evaluated and fetal nutritional stores at birth will be analyzed. • The infants of both the intervention and control group will be monitored yearly until reaching adulthood (18 years of age). The mothers will be the primary participants since they will be completing the surveys.

23. Methodology: • Follow-up studies will be completed by annual physicals at the infant’s check-ups with physicians. • Complications that may arise will be closely monitored for relevance relating to being born from a hyperemetic mother on Total Parenteral Nutritional Support. • The mothers will complete a survey yearly and send it by email or postal service. The survey will ask the following criteria: any diagnosed chronic diseases documented for your child, does the child have any nutritional related deficiencies, has the child had problems with weight gain/loss, and has the child had problems with growth. • The results will be configured annually each year by a statistician.

24. Methodology:

25. Participants: • The participants of the study were of the female gender and in the age ranges of 18 to 35 years of age for the study. • The age range was chosen based upon possible risk factors that may result from maternal age <18 y/o and >35 y/o • The participants in the intervention group all were hospitalized with the diagnoses of severe hyperemesis gravidarum. These participants were treated with Total Parenteral Nutrition Intravenously throughout pregnancy. • There will be a control group that was not treated with Total Parenteral Nutrition for their diagnoses of severe hyperemesis gravidarum • There will be secondary participants, infants of both the intervention and control group.

26. Lab Measurements: • Maternal weight gain/loss, changes in skin condition(Jaundice), changes in heart rate, blood pressure, electrolyte levels, nutritionally relevant lab values (Iron, Vitamin K, Vitamin A, B Vitamins), Serum Bicarbonate, Urinalysis(Ketones), Liver function tests, White Blood Cells, Thyroid Function test, Hematocrit, Albumin, and Pre-Albumin. Indirect calorimetry for nutritional assessment of nutrient needs during pregnancy. • Annual physical exam results will be monitored by the research team. Infants will have annual medical examination (check-up) with their pediatrician. The pediatrician will monitor for the following values: vitals, presenting complaints, medication changes, functional status, review of lifestyle behaviors and activities, vaccinations and immunizations, growth percentile charts, and nutritionally relevant lab values (Iron, Albumin, PreAlbumin, B vitamins).

27. References: • AbellT., Riely C., Hyperemesis Gravidarum, Journal of Gastroenterology Clinics of North America, 1992, 21(4):835-849 • Allen V., Butler B., Dodds L., Fell D., Outcomes of Pregnancies Complicated by Hyperemesis Gravidarum, Journal of American College of Obstetricians and Gynecologists, 2006, 107(2):285-291 • Allen V., Butler B., Dodds L., Fell D., Risk Factors for Hyperemesis Gravidarum Requiring Hospital Admission During Pregnancy, Journal of American College of Obstetricians and Gynecologists, 2006, 107(2):277-284 • BazerF., Cudd T., Meininger C., Spencer T., Wu G., Maternal Nutrition and Fetal Development, The Journal of Nutrition, 2004, 134(9):2169-2172 • DeitelM., Hew L., Total Parenteral Nutrition in Gynecology and Obstetrics, Journal of Obstetrics and Gynecology, 1980, 55(4):464-468 • BanchikL., Trujilo K., Hyperemesis Gravidarum: Feed the Mother, Feed the Child, Journal of Parenteral and Enteral Nutrition, 2005, 29(2):134-135

28. References: • Buck G., Haughey B., Marecki M., Snell L., Metabolic Crisis: Hyperemesis Gravidarum, Journal of Perinatal and Neonatal Nursing, 1998, 12(2): 204-210 • Sheehan P., Hyperemesis Gravidarum: Assessment and Management, Journal of Australian Family Physician, 2007, 36(9):698-701 • BenottiP., Bistrian B., Blackburn G., Martin R., Trubow M., Hyperalimentation during Pregnancy: A case report, Journal of Parenteral and Enteral Nutrition, 1985, 9(2): 212-215 • JimboM., Hoshi S., Iwasaki M., Okai T., Sugito Y., Cell-Free Fetal DNA is Increased in Plasma of Women with Hyperemesis Gravidarum, Journal of Clinical Chemistry, 2001, 47(12): 2164-2165 • BarkaiG., Farfel Z., Hassin D., Movallem M., Rotman P., Wernickes Encephalopathy in Hyperemesis Gravidarum: Association with Abnormal Liver Function, Israel Journal of Medical Sciences, 1994, 30(3): 225-228 • ChingC., Fejzo M., Goodwin M., MacGibbon K., Mullin P., Risk Factors, Treatments and Outcomes Associated with Prolonged Hyperemesis Gravidarum, Journal of Maternal-Fetal and Neonatal Medicine, 2011, 1(5): 251-254 • SonkusareS., The Clinical Management of Hyperemesis Gravidarum, Journal of Obstetrics and Gynecology, 2011, 283: 1183-1192

29. References: • AubryR., Brown H., Folk J., Nosouition J., Silverman R., Hyperemesis Gravidarum: Outcomes and Complications with and without Total Parenteral Nutrition, Journal of Nutritional Clinical Practice, 2005, 20(3): 364-365 • JueckstockJ., Kaestner R., Mylonas I., Managing Hyperemesis Gravidarum: A Multimodal Challenge, Journal of BMC Medicine, 2010, 8: 46-48 • Novak D., Nutrition in early life. How important is it?, Journal of Clinics in Perinatology, 2002, 29(2): 203-223