Nausea and Vomiting of Pregnancy and its Management with the Dual-Release Formulation of Doxylamine and Pyridoxine

Abstract

Nausea and vomiting of pregnancy (NVP) is among the most common conditions that pregnant women encounter in the early stages of pregnancy. It can affect up to 85% of pregnant women, thus representing a significant public health concern. NVP results in substantial negative physical, emotional, and financial consequences. Despite its prevalence, the pathogenesis remains elusive. Few guidelines have been published; however, several interventions exist for the symptomatic treatment of NVP.

The aim of this review is to provide an overview of modern treatment strategies of NVP with a special focus on the recently approved dual-release formulation of the doxylamine and pyridoxine combination. This combination was approved by the Food and Drug Administration (FDA) in November 2016 for the treatment of NVP when conservative management fails, and it has been introduced to the American market in April 2018.

The maximum plasma concentration (T_max) of doxylamine and pyridoxal-5-phosphate is reached 3.5 h and 15 h, respectively, after administration of one tablet twice daily, or 4.5 h and 0.5 h, respectively, when one tablet is administered just once daily.

In addition, the delayed-release combination allows sufficient levels of doxylamine and the active metabolite pyridoxal-5-phosphate in the systemic circulation, providing symptoms relief in the subsequent morning.

Hence, the dual-release formulation can improve the quality of life of pregnant women suffering from NVP. Additionally, large epidemiological trials have shown no increased risk of adverse effects to newborns, demonstrating that its use is not teratogenic.

Zusammenfassung

Übelkeit und Erbrechen in der Schwangerschaft (Nausea and Vomiting of Pregnancy, NVP) gehören zu den häufigsten Schwangerschaftsbeschwerden, mit denen schwangere Frauen in der Frühschwangerschaft zu kämpfen haben. Bis zu 85% aller schwangeren Frauen können davon betroffen sein; diese Beschwerden stellen somit ein wichtiges Gesundheitsproblem dar. NVP kann beträchtliche negative physische, emotionelle und finanzielle Konsequenzen haben. Trotz der weiten Verbreitung von NVP ist die Pathogenese immer noch unklar. Bislang wurden nur wenige Leitlinien dazu veröffentlicht; es gibt aber mehrere Interventionen zur Behandlung der Symptome von NVP.

Ziel dieser Übersichtsarbeit war es, einen Überblick der modernen Strategien zur Behandlung von NVP zu geben, mit einem besonderen Schwerpunkt auf die kürzlich zugelassene duale Wirkstoffkombination von Doxylamin und Pyridoxin. Diese Wirkstoffkombination wurde im November 2016 von der US-amerikanischen Zulassungsbehörde FDA (Food and Drug Administration) zur Behandlung von NVP bei Versagen von konservativen Managementstrategien zugelassen und kam im April 2018 auf den US-amerikanischen Markt.

Die maximale Plasmakonzentration (T_max) von Doxylamin und Pyridoxin stellt sich ca. 3,5 bzw. 15 Stunden nach Einnahme einer Tablette, die 2-mal am Tag verabreicht wird, ein und 4,5 bzw. 9 h Stunden nach Einnahme einer Tablette, wenn nur 1 Tablette am Tag eingenommen wird.

Die Verzögerung bei der Freisetzung der Wirkstoffe bedeutet, dass der Blutspiegel von Doxylamin und dem aktiven Metaboliten Pyridoxal-5-Phosphat in der systemischen Zirkulation ausreicht, um eine Symptomlinderung auch am nächsten Morgen zu gewährleisten.

Diese Wirkstoffkombination mit dualer Freisetzung kann folglich die Lebensqualität von schwangeren Frauen, die unter NVP leiden, verbessern. Hinzu kommt, dass große epidemiologische Studien kein erhöhtes Risiko für negative Auswirkungen auf Neugeborene feststellen konnten; dies zeigt, dass diese Wirkstoffkombination nicht teratogen ist.

Keywords

pregnancy - nausea and vomiting of pregnancy - emesis - doxylamine - pyridoxine

Schlüsselwörter

Schwangerschaft - Übelkeit und Erbrechen in der Schwangerschaft - Emesis - Doxylamin - Pyridoxin

• References

• 1 Bustos M, Venkataramanan R, Caritis S. Nausea and vomiting of pregnancy – What’s new?. Auton Neurosci 2017; 202: 62-72
• 2 Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993; 43: 245-248
• 3 Whitehead SA, Andrews PLR, Chamberlain GVP. Characterisation of nausea and vomiting in early pregnancy: a survey of 1000 women. J Obstet Gynaecol 1992; 12: 364-369
• 4 Einarson TR, Piwko C, Koren G. Quantifying the global rates of nausea and vomiting of pregnancy: a meta analysis. J Popul Ther Clin Pharmacol 2013; 20: e171-e183
• 5 Clark S, Hughes B, McDonald SS. The impact of nausea and vomiting of pregnancy on quality of life: Report of a national consumer survey and recommendations for improving care. Obstet Gynecol Surv 2013; 68 (Suppl. 1) S1-S10
• 6 Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: A prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2000; 182: 931-937
• 7 Vellacott ID, Cooke EJ, James CE. Nausea and vomiting in early pregnancy. Int J Gynaecol Obstet 1988; 27: 57-62
• 8 Coronado PJ, Fasero M, Alvarez-Sanchez A. et al. Prevalence and persistence of nausea and vomiting along the pregnancy. Rev Esp Enferm Dig 2014; 106: 318-324
• 9 Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in pregnancy. BMJ 2011; 342: d3606
• 10 APGO. Nausea and Vomiting of Pregnancy. (APGO Educational series on women’s health issues; ). Boston: Jespersen & Associates, LLC; 2013
• 11 Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstet Gynecol 2018; 131: e15-e30
• 12 Fejzo MS, Trovik J, Grooten IJ. et al. Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nat Rev Dis Primers 2019; 5: 62
• 13 d’Hauterive SP, Close R, Gridelet V. et al. Human Chorionic Gonadotropin and Early Embryogenesis: Review. Int J Mol Sci 2022; 23: 1380
• 14 Gridelet V, Perrier d’Hauterive S, Polese B. et al. Human Chorionic Gonadotrophin: New Pleiotropic Functions for an “Old” Hormone During Pregnancy. Front Immunol 2020; 11: 343
• 15 Lacasse A, Rey E, Ferreira E. et al. Epidemiology of nausea and vomiting of pregnancy: prevalence, severity, determinants, and the importance of race/ethnicity. BMC Pregnancy Childbirth 2009; 9: 26
• 16 Semmens JP. Female sexuality and life situations. An etiologic psycho-socio-sexual profile of weight gain and nausea and vomiting in pregnancy. Obstet Gynecol 1971; 38: 555-563
• 17 Klebanoff MA, Koslowe PA, Kaslow R. et al. Epidemiology of vomiting in early pregnancy. Obstet Gynecol 1985; 66: 612-616
• 18 Weigel RM, Weigel MM. Nausea and vomiting of early pregnancy and pregnancy outcome. A meta-analytical review. Br J Obstet Gynaecol 1989; 96: 1312-1318
• 19 Lee NM, Saha S. Nausea and vomiting of pregnancy. Gastroenterol Clin North Am 2011; 40: 309-334
• 20 Koren G, Boskovic R, Hard M. et al. Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol 2002; 186: S228-S231
• 21 Koren G, Piwko C, Ahn E. et al. Validation studies of the Pregnancy Unique-Quantification of Emesis (PUQE) scores. J Obstet Gynaecol 2005; 25: 241-244
• 22 Lacasse A, Rey E, Ferreira E. et al. Validity of a modified Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scoring index to assess severity of nausea and vomiting of pregnancy. Am J Obstet Gynecol 2008; 198: 71.e1-71.e7
• 23 O’Brien B, Relyea MJ, Taerum T. Efficacy of P6 acupressure in the treatment of nausea and vomiting during pregnancy. Am J Obstet Gynecol 1996; 174: 708-715
• 24 Rhodes VA, Watson PM, Johnson MH. Development of reliable and valid measures of nausea and vomiting. Cancer Nurs 1984; 7: 33-41
• 25 Zhou Q, O’Brien B, Soeken K. Rhodes Index of Nausea and Vomiting--Form 2 in pregnant women. A confirmatory factor analysis. Nurs Res 2001; 50: 251-257
• 26 Melzack R, Rosberger Z, Hollingsworth ML. et al. New approaches to measuring nausea. CMAJ 1985; 133: 755-758
• 27 Swallow BL, Lindow SW, Masson EA. et al. Development of an instrument to measure nausea and vomiting in pregnancy. J Obstet Gynaecol 2002; 22: 481-485
• 28 Swallow BL, Lindow SW, Masson EA. et al. Women with nausea and vomiting in pregnancy demonstrate worse health and are adversely affected by odours. J Obstet Gynaecol 2005; 25: 544-549
• 29 Mohamadi S, Garkaz O, Abolhassani M. et al. The Relationship of Nausea and Vomiting during Pregnancy with Pregnancy Complications. J Midwifery Reproductive Health 2020; 8: 2310-2316
• 30 Mitchell-Jones N, Gallos I, Farren J. et al. Psychological morbidity associated with hyperemesis gravidarum: a systematic review and meta-analysis. BJOG 2017; 124: 20-30
• 31 Tan A, Lowe S, Henry A. Nausea and vomiting of pregnancy: Effects on quality of life and day-to-day function. Aust N Z J Obstet Gynaecol 2018; 58: 278-290
• 32 Gadsby R, Rawson V, Dziadulewicz E. et al. Nausea and vomiting of pregnancy and resource implications: the NVP Impact Study. Br J Gen Pract 2019; 69: e217-e223
• 33 Heitmann K, Nordeng H, Havnen GC. et al. The burden of nausea and vomiting during pregnancy: severe impacts on quality of life, daily life functioning and willingness to become pregnant again – results from a cross-sectional study. BMC Pregnancy Childbirth 2017; 17: 75
• 34 Attard CL, Kohli MA, Coleman S. et al. The burden of illness of severe nausea and vomiting of pregnancy in the United States. Am J Obstet Gynecol 2002; 186: S220-S227
• 35 Mazzotta P, Stewart DE, Koren G. et al. Factors associated with elective termination of pregnancy among Canadian and American women with nausea and vomiting of pregnancy. J Psychosom Obstet Gynaecol 2001; 22: 7-12
• 36 Miller F. Nausea and vomiting in pregnancy: the problem of perception–is it really a disease?. Am J Obstet Gynecol 2002; 186: S182-S183
• 37 Laitinen L, Nurmi M, Rautava P. et al. Sleep quality in women with nausea and vomiting of pregnancy: a cross-sectional study. BMC Pregnancy Childbirth 2021; 21: 152
• 38 Campbell K, Rowe H, Azzam H. et al. The Management of Nausea and Vomiting of Pregnancy. J Obstet Gynaecol Can 2016; 38: 1127-1137
• 39 Jones JM, Qin R, Bardia A. et al. Antiemetics for chemotherapy-induced nausea and vomiting occurring despite prophylactic antiemetic therapy. J Palliat Med 2011; 14: 810-814
• 40 Sanger GJ, Andrews PLR. A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research. Front Pharmacol 2018; 9: 913
• 41 Royal College of Obstetricians and Gynaecologists. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum (Green-top Guideline No. 69). London: RCOG; 2016. Accessed February 16, 2023 at: https://www.rcog.org.uk/en/guidelines-researchservices/ guidelines/gtg69/
• 42 Arsenault MY, Lane CA, MacKinnon CJ. et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can 2002; 24: 817-831
• 43 Einarson A, Maltepe C, Boskovic R. et al. Treatment of nausea and vomiting in pregnancy: an updated algorithm. Can Fam Physician 2007; 53: 2109-2111
• 44 Levichek Z, Atanackovic G, Oepkes D. et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002; 48: 267-268
• 45 Gilboa SM, Ailes EC, Rai RP. et al. Antihistamines and birth defects: a systematic review of the literature. Expert Opin Drug Saf 2014; 13: 1667-1698
• 46 Holmes LB. Teratogen update: bendectin. Teratology 1983; 27: 277-281
• 47 Koren G, Clark S, Hankins GD. et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol 2010; 203: 571.e1-571.e7
• 48 Pope E, Maltepe C, Koren G. Comparing pyridoxine and doxylamine succinate-pyridoxine HCl for nausea and vomiting of pregnancy: A matched, controlled cohort study. J Clin Pharmacol 2015; 55: 809-814
• 49 Flake ZA, Linn BS, Hornecker JR. Practical selection of antiemetics in the ambulatory setting. Am Fam Physician 2015; 91: 293-296
• 50 Matok I, Clark S, Caritis S. et al. Studying the antiemetic effect of vitamin B6 for morning sickness: pyridoxine and pyridoxal are prodrugs. J Clin Pharmacol 2014; 54: 1429-1433
• 51 Zhang R, Persaud N. 8-Way Randomized Controlled Trial of Doxylamine, Pyridoxine and Dicyclomine for Nausea and Vomiting during Pregnancy: Restoration of Unpublished Information. PLoS One 2017; 12: e0167609
• 52 Matthews A, Dowswell T, Haas DM. et al. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2010; (09) CD007575
• 53 Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie Institut für Klinische Pharmakologie und Toxikologie, Charité – Universitätsmedizin, Campus Virchow-Klinikum. Embryotox 2023 Accessed January 12, 2024 at: https://www.embryotox.de/
• 54 McKeigue PM, Lamm SH, Linn S. et al. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994; 50: 27-37
• 55 Brent RL. Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol 1995; 9: 337-349
• 56 Madjunkova S, Maltepe C, Koren G. The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin®) for the treatment of nausea and vomiting of pregnancy. Paediatr Drugs 2014; 16: 199-211
• 57 Kutcher JS, Engle A, Firth J. et al. Bendectin and birth defects. II: Ecological analyses. Birth Defects Res A Clin Mol Teratol 2003; 67: 88-97
• 58 Brent R. Bendectin and birth defects: hopefully, the final chapter. Birth Defects Res A Clin Mol Teratol 2003; 67: 79-87
• 59 Nuangchamnong N, Niebyl J. Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview. Int J Womens Health 2014; 6: 401-409
• 60 Exeltis Germany GmbH. Xonvea 20 mg/20 mg magensaftresistente Tabletten. Summary of product characteristics. 2023 Accessed January 12, 2024 at: https://www.exeltis.de/produkte/kinderwunsch-schwangerschaft/xonvea-20-mg-20-mg
• 61 Boskovic R, Einarson A, Maltepe C. et al. Diclectin therapy for nausea and vomiting of pregnancy: effects of optimal dosing. J Obstet Gynaecol Can 2003; 25: 830-833
• 62 FDA. Center for Drug Evaluation and Research: NDA 209661 Clinical Pharmacology and Biopharmaceutics Review(s). 2016 Accessed January 12, 2024 at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209661Orig1s000ClinPharmR.pdf
• 63 Koren G, Vrandrick M. Treating Symptoms of Morning Sickness: The First Dual Release Combination of Doxylamine-Pyridoxine. Int J Pharm 2018; 8: 52-58
• 64 Costantine MM, Matok I, Chiossi G. et al. Determinants of adherence to delayed-release doxylamine and pyridoxine in patients with nausea and vomiting of pregnancy. Ther Drug Monit 2012; 34: 569-573