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Nausea and Vomiting of Pregnancy: Cases for Pharmacological Consideration

Nausea and Vomiting of Pregnancy: Cases for Pharmacological Consideration. Educational Support & CME. Educational Support An educational grant to support this program has been provided by Duchesnay USA. Continuing Medical Education (CME) Credit

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Nausea and Vomiting of Pregnancy: Cases for Pharmacological Consideration

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  1. Nausea and Vomiting of Pregnancy: Cases for Pharmacological Consideration

  2. Educational Support & CME • Educational Support • An educational grant to support this program has been provided by Duchesnay USA. • Continuing Medical Education (CME) Credit • An accredited, multimedia presentation is available online at NVPCases.com • Physicians and Nurses can earn 1.0 hours CME credit.

  3. Clinical Trial Experiences With NVP

  4. Gary D.V. Hankins, MDGarland D. Anderson, MD Distinguished University Chair in Maternal Fetal MedicineProfessor and Chairman,Department of Obstetrics & GynecologyUniversity of Texas Medical BranchGalveston, Texas

  5. Nausea and Vomiting of Pregnancy • Nausea and vomiting of pregnancy (NVP) is a spectrum disorder with varying degrees of symptoms1 • NVP, commonly known as morning sickness, occurs in approximately 75%-80% of pregnant women2 • Symptoms range from mild to severe • Severe NVP (hyperemesis gravidarum [HG]) is seen in approximately 1-3% of pregnancies3 • Self-limiting condition with no impact on long-term health1 1Badell ML, Ramin SM, Smith JA. Pharmacotherapy.2006;26:1273-87.2Gadsby R, Barnie-Adshead AM, Jagger C. Br J Gen Pract. 1993;43:245-8. 3Tsang IS, Katz VL, Wells SD. Int J Gynaecol Obstet. 1996;55:231-5.

  6. Prevalence of NVP Percentage of Women Experiencing Symptoms Nausea 50%-90% Vomiting 25%-50% NVP 70%-85% Recurrent NVP in subsequent pregnancy 80%-85% 0 10 20 30 40 50 60 70 80 90 100 Einarson TR, Navioz Y, Maltepe C et al. J Obstet Gynaecol. 2007;27(4):360-2. Erick M. OBG Management. 2000;25-35. Gadsby R, Barnie-Adshead AM, Jagger C. Br J Gen Pract. 1993;43:245-8. Koren G, Maltepe C. J Obstet Gynaecol. 2004;24(5):530-3. O’Brien B, Zhou Q. Birth. 1995;22:93-100.

  7. 40% of Pregnancies Result in Clinically Significant NVP 40% Gadsby R, Barnie-Adshead AM, Jagger C. Br J Gen Pract. 1993;43:245-8. O’Brien B, Zhou Q. Birth. 1995;22:93-100. Vellacott ID, Cooke EJA, James CE. Int J Gynecol Obstet. 1988;27:57-62.

  8. Medical, Economic, & Social Impacts • Quality of life (QOL) and work efficiency are adversely affected by NVP.1 • When QOL measures are used in research studies, the scores for women with NVP are worse than the scores of women who report chronic depression.2 • A 2002 study estimated reduced productivity, visits to health care professionals, and the cost of medications and other remedies at $2947 per woman with moderate to severe NVP. 2 • Severe NVP is estimated at approximately $130 million/year from hospital visits alone.3 1O'Brien B, Naber S. Birth. 1992;19:138–43. 2Attard CL, Kohli MA, Coleman S et al. Am J Obstet Gynecol. 2002;186(5 suppl):S220–7. 3Miller F. Am J Obstet Gynecol. 2002;186(5 suppl):S182-3.

  9. Impact of NVP Caused Depression Required Time Off Work Relationships Affected Work Affected 1O'Brien B, Naber S. Birth. 1992;19:138–43. 2Miller F. Am J Obstet Gynecol. 2002;186(5 suppl):S182–3.

  10. Effectiveness of Delayed-Release Doxylamine + Pyridoxine for NVP: A Randomized Placebo Controlled Trial • Objective • Evaluate the effectiveness ofdoxylaminesuccinate10 mg-pyridoxine hydrochloride 10 mg (delayed-release preparation; Diclectin®), as compared with placebo for nausea and vomiting of pregnancy. • Study design • A randomized, double-blind, multicenter placebo controlled trial studying pregnant women suffering from NVP, analyzed by intention to treat. • Women received active drug (N = 131) or placebo (N = 125) for 14 days • NVP symptoms were evaluated daily using the Pregnancy Unique Quantification of Emesis (PUQE) scale. Koren G, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  11. Pregnancy Unique-Quantification of Emesis and Global Assessment of Well-being Koren G, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  12. Subject Enrollment & Final Study Disposition Koren G, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  13. Doxylamine succinate/pyridoxine hydrocholoride (Diclectin®): Phase 3 Efficacy Score Pregnancy-Unique Quantification of Emesis/Nausea (PUQE) index: Total score is sum of replies to each of the 3 questions. Nausea Score: Mild NVP = ≤6; Moderate NVP = 7 to 12; Severe NVP = ≥ 13. http://clinicaltrials.gov/ct2/show/results/NCT00614445?term=diclectin&rank=1&sect=X436015#othr. KorenG, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  14. Primary Endpoint Koren G, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  15. Secondary Endpoints Women receiving placebo were 50% more likely to report use of alternate therapies and dietary modification. Koren G, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  16. Adverse Events Profile http://clinicaltrials.gov/ct2/show/results/NCT00614445?term=diclectin&rank=1&sect=X436015#othr. KorenG, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  17. Adverse Events Profile KorenG, Clark S, Hankins GDV et al. Am J ObstetGynecol. 2010;203:571.e1-7.

  18. Effectiveness of Delayed-Release Doxylamine + Pyridoxine for NVP: A Randomized Placebo Controlled Trial • Significant improvement over placebo • Change in PUQE baseline to day 15 • Global assessment of well-being baseline to day 15 • Day-to-day changes in PUQE & global assessment of well-being • Significantly superior to placebo • Continue treatment on a compassionate basis • Women receiving placebo • Reported 50% > use of alternate therapies and dietary modification • No increase in adverse effects compared with placebo (somnolence, back pain) Koren G, Clark S, Hankins GDV et al. Am J Obstet Gynecol. 2010;203:571.e1-7.

  19. Drugs in Pregnancy

  20. Gideon Koren MD, FRCPC, FACMT Director, The Motherisk Program The Hospital for Sick Children, Professor of Pediatrics, Pharmacology, Pharmacy and Medical Genetics; Professor of Medicine, Pediatrics and Physiology/Pharmacology; Ivey Chair in Molecular Toxicology The University of Toronto Toronto, Ontario, Canada

  21. Drugs in Pregnancy: The Issues • Only half of all pregnancies are planned. • Many women need medications for pregnancy induced conditions (e.g. morning sickness), chronic conditions (e.g. epilepsy), and intercurrent conditions (e.g. allergies). • Women work with chemicals, are exposed to radiation, and use illicit drugs. • During embryogenesis, drugs and chemicals may adversely affect development.

  22. Situational Analysis • Anxiety of birth defects • Leads women not to take medications during pregnancy and lactation. • Leads pharmaceutical companies not to develop drugs for pregnant and lactating women. • Women are not treated appropriately even after the first trimester, or for life threatening conditions.

  23. Perception of Teratogenic Risk • Even when exposed to non teratogenic drugs,women assign a 25% teratogenic risk.1 • Evidence-based counseling can prevent unnecessary pregnancy terminations.2 1Koren G, Bologa M, Long D et al. Am J Obstet Gynecol. 1989;160(5 Pt 1):1190-4. 2Koren G, Pastuszak A. Teratology. 1990;41(6):657-61.

  24. Nausea and Vomiting of Pregnancy • NVP affects 80% of pregnant women. • Doxylamine-pyridoxine (Bendectin®) was used by 40% of pregnant American women in 1978. • Due to litigations, drug removed in 1983 despite scientific and FDA support. • Meta-analysis: OR 1.01 (0.66-1.55) • In Canada: Delayed-release doxylamine/pyridoxine (Diclectin®) use is increasing with a temporal decrease in hospitalizations. Einarson TR, Leeder JS, Koren G. Drug Intell Clin Pharm. 1988;22(10):813-24.

  25. U.S. Temporal Trends for Limb Reduction Deformities, Bendectin® Sales, and Hospitalizations for NVP 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Hospitalization Trend Limb Reduction Deformities Bendectin® Sales 74 76 78 80 82 84 86 88 Year Neutel CI, Johansen HL. Can J Public Health. 1995;86(1):66-70.

  26. Rate of Hospitalization in Canada 20 18 16 14 12 10 8 150 100 50 0 Bendectin® Hospitalizations for EVP Hospitalizations/1000 Births Prescriptions in 1000s Diclectin® 80 82 84 86 88 90 92 94 96 Year EVP = Excessive Vomiting in Pregnancy Neutel CI, Johansen HL. Can J Public Health. 1995;86(1):66-70.

  27. Motherisk-NVP Line • The only counseling health line worldwide for women suffering from NVP. • 1-800-436-8477 (Canada & USA) • Evidence-based counseling on drug safety, effectiveness for symptom management • Large prospective database for research

  28. Which Drugs Are Safe for NVP? • Diclectin®/Bendectin®based on over 250,000 women f/u • Safe even at doses up to 8 tab/d1 • Other antihistamines2 • Odds ratio: 0.76 (0.6-0.94) • Ondansetron -- possibly safe, based on GlaxoSmithKline postmarketing, Motherisk controlled study (N = 169) and Danish study (N = 4000) • Metoclopramide -- safe based on large numbers3 1Atanackovic G, Navioz Y, Moretti ME, Koren G. J Clin Pharmacol. 2001;41:842-5.2Seto A, Einarson T, Koren G. Am J Perinatol. 1997;14:119-24. 3Matok I, Gorodischer R, Koren G et al. N Engl J Med. 2009;360:2528-35.

  29. Which Drugs Are Safe for NVP? • Phenothiazines -- probably safe based on several series1 • Ginger -- safe2 • Pyridoxine -- safe even at large doses (50-500)3 1Magee LA, Mazzotta P, Koren G. Am J Obst Gynecol. 2002;186:S256-61.2Portnoi G, Chng LA, Karimi-Tabesh L et al.Am J Obst Gynecol. 2003;189:1374-7.3Shrim A, Boskovic R, Maltepe C et al. J Obstet Gynaecol. 2006;26:749-51.

  30. Psychosocial Morbidity in NVP • More severe NVP • More measured depression • Considering termination of pregnancy • Adverse relationships • Adverse effects on partners • Perception of NVP harming the baby • N = 3201 • Mazzotta P, Stewart D, Atanackovic G et al.J Psychosom Obstet Gynaecol. 2000;21:129-36.

  31. Factors Associated With Pregnancy Termination in NVP • N = 3201 • N = 413 considered termination • N = 108 terminated “due to NVP” • Independent factors with women considering termination • Unplanned pregnancy • More severe vomiting • Feeling of depression • Partner’s daily life • Relationship with partner • Mazzotta P, Stewart D, Atanackovic G et al.J Psychosom Obstet Gynaecol. 2000;21:129-36.

  32. Pregnancy Termination • Factors independently associated with termination • Unplanned pregnancy • Multiparity • Depression • These factors should be considered when managing these women • Mazzotta P, Stewart D, Atanackovic G et al.J Psychosom Obstet Gynaecol. 2000;21:129-36.

  33. Preemptive Therapy for NVP • After doxylamine/pyridoxine (Bendectin®) d/c • Three-fold more cases of hospitalization for severe NVP • Suggests that symptom treatment prevents deterioration of cases. • Preemptivestudy (N = 25) • Women reporting severe NVP in a previous pregnancy are “afraid to conceive again.” • Commenced using antiemetics upon becoming aware of pregnancy. Koren G, Maltepe C. J Obst Gyn. 2004;24:530-3.

  34. Preemptive Study • Matched to 35 women counseled regularly when symptoms started • Severe NVP decreased from 18 to 8 cases (P = 0.01) • No such change in the comparison group • In the control group-unchanged severe NVP (80%) when compared to previous pregnancy • Presently, a randomized controlled clinical trial with delayed-release doxylamine/pyridoxine (Diclectin®) is in progress. Koren G, Maltepe C. J Obst Gyn. 2004;24:530-3.

  35. Doxylamine/Pyridoxine (Diclectin®) Preemptive Prospective Trial • Women with severe NVP in previous pregnancy • Randomized to receive (Diclectin®) either before NVP started, or at the outset of symptoms • Preemptive group had less severe symptoms in first weeks. • Overall more cases that NVP stopped before labor Maltepe C, Koren G. Obstet Gynecol Int. 2013;2013:809787.

  36. Preemptive Prospective • Significant reduction in episodes of severe NVP • Both groups received similar personalized approach of counseling: • Nutritional changes • Acid reflux treatment • All physicians had to be part of the circle of care. Maltepe C, Koren G. Obstet Gynecol Int. 2013;2013:809787.

  37. Acid Reflux in NVP • Women with acid reflux during NVP • Significantly more severe symptoms of nausea, vomiting, and retching • Increased in acid reflux in pregnancy • Intra-abdominal pressure, progesterone • Treatment with histamine-2 blockers or proton pump inhibitors significantly reduced symptoms Gill SK, Maltepe C, Mastali K, Koren G. Obstet Gynecol Int. 2009;2009:585269.

  38. Conclusions • The return of doxylamine/pyridoxine (Diclegis®), a known and safe drug for NVP, will be welcomed by the obstetric community and pregnant women. • Trivialization of NVP must be replaced by individualized management which includes pharmacotherapy and non-pharmacological means.

  39. Patient Case Studies

  40. Jennifer R. Niebyl, MDProfessor and Vice Chair for ObstetricsDepartment of Obstetrics and GynecologyThe University of Iowa Carver College of MedicineIowa City, Iowa

  41. Case #1 • 32-year old female in 1st trimester of pregnancy • Frequency of nausea is generally throughout the day • Frequency of vomiting is 1-2 times daily in the morning • Doesn’t feel good enough to go to work • Steady weight loss over the last couple of weeks

  42. Case #1 • Phones physician’s office because of NV • Patient wants to know what she can do to get rid of her NV • Patient does not want to come into the office • Can she be managed clinically over the phone? • What additional information do we need from the patient? Any headache, abdominal pain, fever? • What are the first steps in treating her?

  43. Clinical Management of NVP • Avoid odors, triggers • Avoid fatty, spicy foods • Omit iron tablets • Frequent small feedings, fluids between meals • Bland and dry, high-protein foods • Crackers at bedside in AM • Avoid empty stomach

  44. Clinical Management of NVP • Large ketones • Intermittent IV hydration (with multivitamins) • LFTs, amylase, urinalysis, electrolytes • Follow urinary ketones, weight, electrolytes • Ultrasound • Multiple gestation • Hydatidiform mole • Antiemetics • Prevent parenteral nutrition

  45. Case #1 • Follow-up with patient reveals NV not subsided • Patient declines medication • Pyridoxine (vitamin B6), PrimaBella®, ginger • Alternative therapies are offered

  46. Treatment of NVP: Pyridoxine (Vitamin B6) • Sahakian et al. • 25 mg (1/2 tab) PO Q8hrs or placebo (N = 59) • ~ 50% of patients stopped vomiting • Severe nausea decreased to mild or moderate • No effect on mild nausea • Vutyavanich et al. • 30 mg/d PO versus placebo x 5 d (N = 342) • Significant decrease in nausea (P < 0.008) • No. of vomiting episodes reduced (P = 0.0552) Sahakian V, Rouse D, Sipes S et al. Obstet Gynecol. 1991;78:33-6. Vutyavanich T, Wongtra-ngan S, Ruangsri R.Am J Obstet Gynecol. 1995;173:881-4.

  47. Treatment of NVP • Pyridoxine + doxylamine (not delayed release like Bendectin®, Diclectin®, Diclegis®) • Pyridoxine (vitamin B6) 50-mg tablets • 1/2 tablet TID • Doxylamine (Unisom SleepTabs®) 25 mg • 1 tablet QHS; 1/2 tablet in AM and PM PRN • Lack of teratogenicity McMahon MJ in Yankowitz J & Niebyl JR: Drug Therapy in Pregnancy. Lippincott, Williams & Wilkins, Philadelphia, 2001:p. 81.

  48. Delayed-Release Pyridoxine/Doxylamine • FDA approved Diclegis® on April 8, 2013 • Delayed-release pyridoxine 10 mg + doxylamine 10 mg • FDA category A for pregnancy • 2 tablets QHS, 1 tablet QAM PRN • +1 tablet QPM PRN • Only FDA-approved treatment for NVP

  49. Acupuncture in NVP • Two randomized trials • N = 33, Sweden, versus placebo acupuncture1 • Different site and superficial • Helped hyperemesis gravidarum (HG) • N = 55, England, traditional acupuncture versus sham2 • Blunt cocktail stick over different area and dressing • Nausea  vomiting, outpatients, no difference 1Knight B, Mudge C, Openshaw S et al. Obstet Gynecol. 2001;97:184-8. 2Carlsson CP, Axemo P, Bodin A et al. J Pain Symptom Man. 2000;20:273-9.

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